Factor IX deficiency

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Severe hemarthrosis in a young pup with factor IX deficiency[1]

Factor IX ('Christmas factor') deficiency (Type B hemophilia) is an X-linked genetic disease of dogs characterized by spontaneous bleeding.

This disorder is caused by an intron-22 deletion mutation, similar to human hemophilia A[2].

Factor IX deficiency has been reported in the Cairn Terrier, Rhodesian Ridgebacks[3][4], Maltese[5], German Wirehaired Pointer, Bull Terrier and Lhasa Apso[6].

Clinical disease is virtually identical to factor VIII deficiency in dogs, with male dogs presenting with hematomas, hemarthrosis, gingival bleeding during tooth eruption, and in severe rare cases, hemoperitoneum or hemothorax.

Affected dogs usually have a range of 4 – 6 spontaneous bleeding episodes per year[7] and bleeding frequency can be used as an efficacy endpoint in treatments to correct the haemophilic coagulopathy.

Female dogs are usually asymptomatic heterozygous carriers.

Stillbirths or neonatal deaths are not uncommon with this disease when factor IX activity is <1%[8].

Diagnosis is usually based on coagulation screening test, which demonstrates a markedly prolonged partial thromboplastin time (usually > 60 seconds), whole blood clotting time[9] and demonstration of <10% normal Factor IX coagulant activity and a proportional reduction of Factor IX protein concentration[10].

A PCR-based genetic technique is also available for identifying the mutation in suspected carriers.

Hemophilia B dogs usually require frequent intravenous whole blood or recombinant or plasma-derived coagulation factor concentrate to treat spontaneous bleeding[11][12] and following invasive procedures to prevent hemorrhage and facilitate wound healing[13].

Long term treatment involves the use of recombinant factor IX or factor VIII[14], often for years, using adjunct gene therapy in cases where spontaneous bleeding becomes more frequent[15].

References

  1. Cornell University
  2. Antonarakis SE (1995) Molecular genetics of coagulation factor VIII gene and hemophilia A. Thromb Haemost 74:322–328
  3. Mischke R et al (2011) G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Vet J 187(1):113-118
  4. 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
  5. Nakata M et al (2006) Hemophilia B in a crossbred Maltese dog. J Vet Med Sci 68(11):1223-1224
  6. Mauser AE et al (1996) A deletion mutation causes hemophilia B in Lhasa Apso dogs. Blood 88:3451–5
  7. Russell KE et al (2003) Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs. Blood 102:4393–4398
  8. Nichols TC et al (2010) Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B. Haemophilia 16(3):19-23
  9. Nichols TC et al (2012) Sensitivity of whole blood clotting time and activated partial thromboplastin time for factor IX: relevance to gene therapy and determination of post-transfusion elimination time of canine factor IX in hemophilia B dogs. J Thromb Haemost 10(3):474-476
  10. Brooks MB et al (2003) A Line 1 insertion in the Factor IX gene segregates with mild hemophilia B in dogs. Mamm Genome 14(11):788-795
  11. Sabatino DE et al (2012) Animal models of hemophilia. Prog Mol Biol Transl Sci 105:151-209
  12. Russell KE et al (2003) Reduced bleeding events with subcutaneous administration of recombinant human factor IX in immune-tolerant hemophilia B dogs. Blood 102:4393–4398
  13. Nichols TC et al (2010) Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B. Haemophilia 16(3):19–23
  14. Sabatino DE et al (2009) Recombinant canine B-domain deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model. Blood 114:4562–4565
  15. Haurigot V et al (2010) Safety of AAV factor IX peripheral transvenular gene delivery to muscle in hemophilia B dogs. Mol Ther 18(7):1318-1329