Hemophilia A (F8 gene, Boxer)

Hemophilia A is the most common inherited bleeding disorder in dogs. When there is a pathogenic mutation in the F8 gene, which produces coagulation factor VIII, the blood clotting process is altered, increasing the risk of uncontrolled bleeding.

Symptoms

Since the F8 gene is located on the X sex chromosome, females carrying one copy of an F8 mutation usually show no symptoms, whereas males do show signs. The severity depends on the levels of residual clotting activity. When factor VIII activity is less than 5%, symptoms usually appear after birth and are more severe. There is spontaneous bleeding into joints and leakage of blood into the body cavity which can be lethal. Prolonged bleeding from the umbilical cord, gums during teething and after surgery is also seen. Dogs with factor VIII activity of 5% to 10% usually do not bleed spontaneously, but bleed more than normal after injury or surgery.

Disease Management

Treatment of hemophilia A focuses on controlling symptoms and preventing severe bleeding. Repeated transfusions of whole blood or plasma are required until the bleeding is controlled. If you suspect your dog may have hemophilia A, it is crucial to take him to a veterinarian for proper diagnosis and treatment.

Genetic basis

This disease follows an X-linked recessive mode of inheritance. Recessive X-linked inheritance means that female dogs must receive two copies of the mutation or pathogenic variant (one from each parent) to develop the disease, whereas males need only one copy of the mutated gene or variant from the dam to develop the disease. Male dogs usually show symptoms of the disease. Each male puppy born to a mother carrying the mutation has a 50% chance of inheriting the mutation and thus the risk of developing the disease. Bitches that do not carry the mutation are not at increased risk of having affected puppies. Breeding between dogs carrying genetic variants that can cause disease, even if they do not show symptoms, is not recommended.

Technical report

The clotting process involves many different proteins, and deficiency of any of these proteins can cause bleeding disorders, such as deficiencies of factor II (prothrombin), factor VII, factor VIII, and factor IX. Deficiency of vitamin K, which is also part of the clotting process, can worsen a clotting defect. Christopherson et al. were the first to detect a nonsense mutation in the F8 gene in German shepherd and Boxer dogs with hemophilia. This was the c.1469C>G variant, which results in a single base change at nucleotide position 1469, this affects an amino acid found in the A2 domain of the protein, which is involved in the binding of activated factor IX during coagulation. Mutations affecting this same domain have been observed in human coagulation factor VIII that are associated with a significant reduction in factor VIII activity (below 1%).

Most affected breeds

Boxer
Cocker Spaniel
German Shepherd Dog
German Shorthaired Pointer
Golden Retriever
Irish Setter
Malinois
Miniature Schnauzer
Old English Sheepdog
Poodle
Rhodesian Ridgeback
Siberian Husky
Weimaraner

Bibliography

Christopherson PW, Bacek LM, King KB,et al. Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog. Vet Clin Pathol. 2014 Sep;43(3):312-6.