Factor VIII Deficiency, Hemophilia A

Hemophilia is an inherited deficiency in a single blood-clotting factor. The two most common types, hemophilia A and hemophilia B, are caused by recessive genes on X chromosome. Females have two X chromosomes. If they have one normal and one abnormal gene they will not show signs of hemophilia. Males have one X chromosome and one Y chromosome and get their X chromosome from their mother, so about 50% of male puppies born to a female dog who is a carrier of hemophilia gene will have the disease.1 If hemophilic males are bred to carrier females, hemophilic females can also be produced. It is important to diagnose carrier because they should be removed from breeding programs.

Hemophilia A is a factor VIII deficiency, and hemophilia B is a factor IX deficiency. Which type a dog has is determined by measuring the amounts of these factors in the blood. The amount of factor VIII a dog with hemophilia A produces can range from none to 25% of normal. The severity of the disease depends on the concentration of factor VIII in blood. Bleeding can be severe if factor VIII activity is less than 5% of normal, or mild, with activity of 5 to 20 % of normal. Sudden bleeding may occur in areas exposed to mechanical pressure, such as joints and muscles. Bleeding under skin, as well as gastrointestinal and urinary bleeding may occur.2 Bleeding into any organ can follow trauma or surgery. In those animals with mild or moderate hemophilia, bleeding is only a problem during and after surgery, or in association with trauma.2 Repeated bleeding into joint spaces, causing painful crippling joint disease that often necessitates joint replacement. Hematomas (collection of blood outside blood vessels) in soft tissues can result in tumor-like formation composed of coagulated blood; they can obstruct, compress, or rupture into adjacent organs and can lead to infection. Once formed the hematomas are difficult to treat, even with surgery. Recovery of nerves after compression is poor, resulting in paralysis of a body part (palsy). Those bleeding episodes that involve the gastrointestinal tract, central nervous system, or airway/abdominal space can lead to death if not detected. Intracranial bleeding is a major cause of death in hemophiliac dogs.5



Bleeding episodes in patients with hemophilia A are treated by transfusing cryoprecipitate, a type of coagulation protein that is lacking, which contains both vWF and factor VIII, as well as fibrinogen and fibrinectin. The therapeutic effect lasts for about a day or less. The infusion duration results in the need for injections twice per week or more to maintain minimal therapeutic levels in the plasma.5 Prophylactic treatment in severe hemophilic dogs by daily injection of relatively high concentrations factor results in a continuous therapeutic level of factor and is accompanied by a two-fold increase in recovery levels by day 5 compared to administration with a single injection.5 Continuous administration of factor using a pump device to provide continuous injection or infusion, however, has the obvious disadvantage that the implantable device or external pump requires frequent servicing and has to be attached to the patient.5

In a substantial number of patients with hemophilia complicated by the development of antibodies against factor VIII or factor IX, cryoprecipitate transfusion therapy is performed with limited success. As alternative to cryoprecipitate, several so-called pro-thrombin complex concentrates containing vitamin K-dependent coagulation factors have been used. However, such concentrates are limited in their effectiveness, and a general supplement with activated coagulation factors is associated with formation of thrombs (clots).

Gene therapy offers the potential of ongoing therapy for dogs with hemophilia A, without relying on repeated infusions of factor VIII which carries the disadvantages of inconvenience, cost and possible risk of contamination.4

chromosome - a structure of DNA, protein, and RNA found in cells
factor VIII - an essential blood-clotting protein, also known as anti-hemophilic factor (AHF)
factor IX - a protein produced naturally in the body that helps the blood form clots to stop bleeding
cryoprecipitate - a component prepared by thawing a unit of fresh frozen plasma at 4ÂșC and then recovering the cold-precipitated factor VIII protein by centrifugation. The usual unit contains an average of 80 units of factor VIII and at least 150 mg of fibrinogen in about 15 mL of plasma.

References

  1. Betsy Brevitz. The Complete Healthy Dog Handbook: The Definitive Guide to Keeping Your Pet
  2. Nemi Chand Jain. Essentials of veterinary hematology
  3. Katherine A. High, Harold Ross Roberts. Molecular basis of thrombosis and hemostasis
  4. Bernard F. Feldman, Joseph G. Zinkl, Nemi Chand Jain, Oscar William Schalm. Schalm's veterinary hematology
  5. Griffith Michael J, Drohan Marian J, Drohan William N. Prophylactic Treatment of Hemophilia