Hemophilia

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Hemophilia is a relatively common genetic disease of dogs[1] and frequently not diagnosed until a surgical procedure results in significant post-operative bleeding.

Haemophilia can be produced by decreased or absent coagulation factors within the blood. These can be congenital or result from a failure to convert procoagulants to coagulants (factors II, VII, IX and X) due to vitamin K absence (cholestatic liver disease or malabsorption syndromes), or vitamin K antagonism (anticoagulant rodenticides) or consumption due to DIC.

A number of types of hemophilia have been recognized in dogs:

  • Genetic clotting factor disorders
- Factor I deficiency (Congenital afibrinogenemia) - Chihuahua[2], Bichon Frise[3], St. Bernard, Borzoi, Vizsla, American Collie
- Factor II deficiency - Boxer, English Cocker Spaniel
- Factor VII deficiency - Airedale Terrier, Alaskan Klee Kai, Beagle, Giant Schnauzer, Scottish Deerhound
- Factor VIII deficiency (Hemophilia A) - Golden Retriever, Havanese, Weimaraner[4], German Shepherd, Chow Chow, Keeshonden, Irish Setter[5]
- Factor IX deficiency (Hemophilia B) - Rhodesian Ridgebacks[6], German Wirehaired Pointer, Bull Terrier, Lhasa Apso
- Factor X deficiency - American Cocker Spaniel, English Springer Spaniel, Jack Russell Terrier - homozygous pups usually die, but heterozygous dogs unaffected[7]
- Factor XI deficiency (Hemophilia C) - Springer Spaniel, Great Pyrenees, Weimaraner, Kerry Blue Terrier[8]
- Factor XII deficiency (Hageman factor) - German Shorthaired Pointer, Standard Poodle, Miniature Poodle
- Von Willebrand's disease[9] - lack of functional von Willebrand factor (vWF) - Corgi, Doberman, German shepherd, German Short-Haired Pointer, Golden Retriever, Shetland Sheepdog, Standard Poodle[10]
  • Hereditary platelet disorders
- Prekallikrein deficiency (Fletcher Trait) - Poodle, Shar Pei[11], German Short-haired Pointer[12], Shih Tzu[13]
- Glanzmann's Thrombasthenia Type I (Thrombasthenia) - Great Pyrenees, Otterhound
- Thrombopathia - Basset Hound[14], Spitz, American Cocker Spaniel[15]
  • Hereditary complement deficiency
- Complement-3 deficiency
  • Acquired platelet disorders
- Thrombocytopenia
- Thrombocytosis
- Rodenticide toxicity

Clinically affected dogs are often young and present with buccal bleeding, epistaxis, rectal bleeding and anemia. There may also be prolonged bleeding from minor wounds and internal hemorrhage involving joints, muscles, and other tissues, with no antecedent trauma. Post-operative bleeding may be the first indication of this disease in some dogs.

Diagnosis is based on hematological signs of anemia, prolonged clotting time, coagulation screening tests (ELISA) and genetic testing[16]. Affected males are accurately diagnosed based on coagulation Factor VIII assays. In contrast, carrier females appear clinically normal and may have Factor VIII values that overlap those of clear females. Hemophilia A is often propagated when these asymptomatic carrier females are used for breeding.

A differential diagnosis would include other causes of bleeding such as aplastic pancytopenia, hemangiosarcoma and Waldenström's macroglobulinemia.

There is no cure for this disorder. Mildly affected dogs may never require treatment, or only after surgery or trauma.

In severely affected dogs, treatment options include periodic fresh or fresh frozen plasma fresh frozen cryoprecipitate (factor VIII) or cryosupernatant (factor IX) plasma[17]. However, the development of neutralizing antibodies to replacement protein is a major complication of protein and enzyme replacement therapies[18].

Recent experiments have shown the efficacy of products such as recombinant factor VIIa[19] or VIII[20].

Gene therapy has shown promise as well[21], utilizing the hyperactive (Sleeping beauty) transposase system to deliver adenoviral-factor VII and IX into the canine liver, resulting in correction of canine hemophilia B[22].

References

  1. Dumont JA et al (2012) Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood 119(13):3024-3030
  2. Chambers G et al (2013) Treatment of afibrinogenemia in a chihuahua. J Am Anim Hosp Assoc 49(1):70-74
  3. Wilkerson MJ et al (2005) Afibrinogenemia and a circulating antibody against fibrinogen in a Bichon Frise dog. Vet Clin Pathol 34(2):148-155
  4. Dunning MD et al (2009) Haemophilia A (factor VIII deficiency) in a litter of Weimaraners. J Small Anim Pract 50(7):357-359
  5. Agersø H et al (2012) Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in hemophilia A dogs. Haemophilia 18(6):941-947
  6. Finn JD et al (2012) The efficacy and the risk of immunogenicity of FIX Padua (R338L) in hemophilia B dogs treated by AAV muscle gene therapy. Blood Aug 23
  7. LIDA
  8. Knowler C et al (1994) Factor XI deficiency in Kerry Blue Terriers. J Am Vet Med Assoc 205(11):1557-1561
  9. Scola MR et al (2011) ARFI ultrasound monitoring of hemorrhage and hemostasis in vivo in canine von Willebrand disease and hemophilia. Ultrasound Med Biol 37(12):2126-2132
  10. Harvey JW, Meyer DJ (1998) Veterinary Laboratory Medicine: Interpretation and Diagnosis.W. B. Saunders Co., Philadelphia, pp.131
  11. Cornell University
  12. Lisciandro, GR et al (2000) Contact factor deficiency in a German Shorthaired Pointer without clinical evidence of coagulopathy. J Vet Intern Med 14:308–310
  13. Okawa T et al (2011) Prekallikrein deficiency in a dog. J Vet Med Sci 73(1):107-111
  14. Johnstone IB & Lotz F (1979) An inherited platelet function defect in basset hounds. Can Vet J 20:211–215
  15. Brooks M & Catalfamo J (1993) Buccal mucosa bleeding time is prolonged in canine models of primary hemostatic disorders. Thromb Haemost 70(5):777-780
  16. Mischke R (2012) Haemophilia A and B in dogs. Tierarztl Prax Ausg K Kleintiere Heimtiere 40(1):44-53
  17. Barr JW & McMichael M (2012) Inherited disorders of hemostasis in dogs and cats. Top Companion Anim Med 27(2):53-58
  18. Finn JD et al (2010) Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood 116(26):5842-5848
  19. Knudsen T et al (2011) Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog. Haemophilia 17(6):962-970
  20. Karpf DM et al (2011) Pharmacokinetics and ex vivo whole blood clot formation of a new recombinant FVIII (N8) in haemophilia A dogs. Haemophilia 17(5):e963-e968
  21. Sabatino DE et al (2011) Efficacy and safety of long-term prophylaxis in severe hemophilia A dogs following liver gene therapy using AAV vectors. Mol Ther 19(3):442-449
  22. Hausl MA et al (2010) Hyperactive sleeping beauty transposase enables persistent phenotypic correction in mice and a canine model for hemophilia B. Mol Ther 18(11):1896-1906