Factor VIII deficiency

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Factor VIII deficiency in a German shepherd, showing hematoma formation in the thigh muscles of his left hind leg[1]

Factor VIII (antihaemophilic factor) deficiency (Type A) is a common X-linked genetic form of canine hemophilia.

Factor VIII is a trace plasma glycoprotein involved as a cofactor in the activation of factor X by factor IXa.

A deficiency in factor VIII is caused by a series of multiple genetic transcript mutations in factor VIII synthesis (the FVIII gene (F8) contains 26 exons and spans 186 kb of DNA[2]). This results in reduced levels and activity of factor VIII[3], leading to abnormal primary thrombocyte plug formations and progressive perivascular bleeding, particularly around highly mobility areas such as joints.

This disease primarily affects male dogs (females are usually heterozygous carriers) and has been reported in the Golden Retriever, Havanese, Weimaraner[4], German Shepherd, German Short-haired Pointer[5], Chow Chow, Keeshonden and Irish Setter[6].

The clinical severity of this condition in dogs is inversely proportional to the circulating factor VIII level in plasma, and severe disease is associated with levels of factor VIII <1% of normal[7].

Clinical symptoms usually involve a predisposition to developing spontaneous hematomas anywhere on the body surface as well as hemoabdomen, hemothorax and hemarthrosis around joints, resulting in lameness and in rare cases, acute paraplegia due to intraspinal hemorrhage[8].

Problems often arise after vaccination, as live vaccines effect the number and function of clotting cells for a period of 10 - 14 days after vaccination. There may be excessive bleeding during teething and puppies may suffer from bloody diarrhoea[9]. Dogs with mild deficiencies may only display hemorrhage associated with trauma or surgery.

Diagnosis is usually based on coagulation screening tests for detection of factor VIII levels[10]. Factor VIII-coagulant (FVIII:C) activity < 0.7 IU m/L is consistent with a diagnosis of hemophilia A[11], although the sensitivity of this assay is only moderate[12][13].

Identification of carriers should be done with caution in animals < 6 months of age (as young animals have lower FVIII:C activities than adults). Carriers usually have a normal APTT and ACT[14].

Treatment of acutely affected dogs requires repeated intravenous injections of fresh frozen cryoprecipitate plasma until bleeding is controlled (usually given at 2 ml/kg)[15].

The experimental use of solulin, a soluble form of thrombomodulin which increases clot lysis time, may be advisable[16].

Desmopressin has been shown to significantly increased factor VIII levels when administered subcutaneously into dogs[17] but in factor VIII deficient dogs, does not correlate with significant increases in serum factor VIII levels[18].

Exercise appears to play an important role in improving hemostasis in dogs affected by this condition, although excessive exercise should not be entertained[19].

Recombinant factor VIII is available[20] as an alternative treatment but is expensive, inconvenient, and complicated by development of antibodies that inhibit FVIII activity within 1 - 2 weeks of therapy[21].

References

  1. Cornell University
  2. Hough C et al (2002) Thromb Haemostasis 87:659–665
  3. Sabatino DE et al (2012) Animal models of hemophilia. Prog Mol Biol Transl Sci 105:151-209
  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. Joseph SA et al (1996) Hemophilia A in a German shorthaired pointer: clinical presentations and diagnosis. J Am Anim Hosp Assoc 32(1):25-28
  6. Agersø H et al (2012) Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in hemophilia A dogs. Haemophilia 18(6):941-947
  7. Lozier JN et al (2002) The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion. Proc Natl Acad Sci U S A 99(20):12991-12996
  8. Thompson MS & Kreeger JM (1999) Acute paraplegia in a puppy with hemophilia A. J Am Anim Hosp Assoc 35(1):36-37
  9. LIDA
  10. Donahue SM et al (2011) Examination of hemostatic parameters to detect hypercoagulability in dogs with severe protein-losing nephropathy. J Vet Emerg Crit Care (San Antonio) 21(4):346-355
  11. Mischke R (2000) Influence of factor VIII:C and factor IX activity in plasmas of haemophilic dogs on the activated partial thromboplastin time measured with two commercial reagents. Haemophilia 6(3):135-139
  12. Mischke R (2000) Sensitivity of the reaction time of the resonance thrombogram for factor VIII:C and factor IX deficiencies in the blood of dogs with haemophilia A or B. Haemophilia 6(5):575-580
  13. Mischke R (1999) Comparison of factor VIII:C and factor IX sensitivity of different commercial APTT reagents for canine plasma. Berl Munch Tierarztl Wochenschr 112(10-11):394-399
  14. Cornell University
  15. Stokol T et al (1997) Pharmacokinetics of von Willebrand factor and factor VIII in canine von Willebrand disease and haemophilia A. Res Vet Sci 63(1):23-27
  16. Foley JH et al (2012) Solulin increases clot stability in whole blood from humans and dogs with hemophilia. Blood 119(15):3622-3628
  17. Sato I & Parry BW (1998) Effect of desmopressin on plasma factor VIII and von Willebrand factor concentrations in Greyhounds. Aust Vet J 76(12):809-812
  18. Mischke R et al (1996) Hemophilia A in the dog: symptoms, blood coagulation analysis and treatment. Berl Munch Tierarztl Wochenschr 109(8):279-287
  19. Othman M et al (2009) Thromboelastography reflects global hemostatic variation among severe haemophilia A dogs at rest and following acute exercise. Haemophilia 15(5):1126-1134
  20. Karpf DM et al (2008) Pharmacokinetics and ex vivo whole blood clot formation of a new recombinant FVIII (N8) in haemophilia A dogs. Haemophilia 17(5):e963-968
  21. 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