Download PDF
Tierarztl Prax Ausg K Kleintiere Heimtiere 2012; 40(01): 44-53
DOI: 10.1055/s-0038-1623619
Übersichtsartikel
Schattauer GmbH

Hämophilie A und B beim Hund[*]

Haemophilia A and B in dogs
R. Mischke
1   Klinik für Kleintiere, Stiftung Tierärztliche Hochschule Hannover
› Author Affiliations
Further Information

Publication History

Eingegangen: 05 December 2011

Akzeptiert nach Revision: 03 January 2012

Publication Date:
05 January 2018 (online)

Also available at
    Permissions and Reprints

Zusammenfassung

Diese Übersichtsarbeit präsentiert anhand eigener klinischer Erfahrungen und der Literatur Aspekte von Ätiologie, Pathogenese, klinischem Bild, Diagnose und Therapie der Hämophilie A und B beim Hund. Im Vergleich zum Menschen zeigen Hunde bei einer definierten Faktor-Restaktivität schwerere Blutungssymptome (u. a. subkutane, intramuskuläre und intraartikuläre Blutungen nach inadäquatem Trauma mit der Folge von Lähmungen und Lahmheiten, exzessive Blutungen bei Zahnwechsel, Venenpunktion und Operationen). Erfreulicherweise sind nun in Deutschland für einige Rassen (Hämophilie B beim Rhodesian Ridgeback, Hämophile A beim Havaneser) kommerziell Gentests verfügbar, die die konventionelle Einzelfaktormessung ergänzen und die Erkennung von Trägerhündinnen erleichtern. Bei der Therapie von Blutungskrisen steht neben lokal blutstillenden Maßnahmen nach wie vor die Substitutionsbehandlung mit frischem Plasma oder gefrorenem Frischplasma im Vordergrund. Hingegen haben sich Erwartungen, die auch beim Menschen in die zeitnahe klinische Verfügbarkeit der Gentherapie gesetzt wurden, bislang nicht erfüllt.

Summary

Based on own clinical experiences and the literature, this review article elaborates on aspects of aetiology, pathogenesis, clinical signs, diagnosis and therapy of haemophilia A and B in dogs. When compared to humans, dogs reveal more severe haemorrhagic symptoms at a defined residual factor activity (e. g. subcutaneous, intramuscular, and intraarticular haemorrhages after inappropriate trauma resulting in lameness and paralysis, excessive haemorrhage during second dentition, venal puncture, and surgery). Fortunately, genetic tests are now commercially available in Germany for selected breeds (haemophilia B in Rhodesian Ridgebacks; haemophilia A in Havaneses), which complement the conventional individual factor activity measurements and facilitate the detection of female carrier dogs. Treatment of bleeding crises is still mainly based on substitution therapy with fresh or fresh frozen plasma in addition to local haemostatic measures. In contrast, expectations regarding the timely clinical availability of gene therapy (particularly in humans) have not yet been fulfilled.

Schlüsselwörter

Hämophilie A - Hämophilie B - Hund - Rassen - Diagnostik - Gentest - Therapie - Literaturübersicht

Key words

Haemophilia A - haemophilia B - dog - breeds - diagnosis - genetic testing - therapy - literature review

* Herrn Prof. Dr. Ingo Nolte zum 60. Geburtstag gewidmet.


 

  • Literatur

  • 1 Aufderheide WM, Skinner SF, Kaneko JJ. Clearance of cryoprecipitated factor VIII in canine hemophilia A. Am J Vet Res 1975; 36: 367-370.
    PubMedSearch in Google Scholar
  • 2 Bellars ARM. Genetic defects in Antarctic dogs. J Small Anim Pract 1971; 12: 493-500.
    CrossrefPubMedSearch in Google Scholar
  • 3 Benn DM, Gentry PA, Johnstone IB. Classical hemophilia (Hemophilia A) in a family of collies. Can Vet J 1978; 19: 221-225.
    PubMedSearch in Google Scholar
  • 4 Boehlen F, Müller PR, Brand B, Von der Weid N, Marbet GA, Tsakiris DA, De Moerloose P. Hämophilie in der Hausarztpraxis. Schweiz Med Forum 2011; 11: 452-457.
    PubMedSearch in Google Scholar
  • 5 Brinkhous KM, Graham JB. Hemophilia in the female dog. Science 1950; 30: 723-724.
    PubMedSearch in Google Scholar
  • 6 Brinkhous KM, Hedner U, Garris JB, Diness V, Read MS. Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease. Proc Natl Acad Sci USA 1989; 86: 1382-1386.
    CrossrefPubMedSearch in Google Scholar
  • 7 Brinkhous KM, Sigman JL, Read MS, Stewart PF, McCarthy KP, Timony GA, Leppanen SD, Rup BJ, Keith Jr JC, Garzone PD, Schaub RG. Recombinant human factor IX: replacement therapy, prophylaxis, and pharmacokinetics in canine hemophilia B. Blood 1996; 07: 2603-2610.
    PubMedSearch in Google Scholar
  • 8 Brooks M. A review of canine inherited bleeding disorders: Biochemical and molecular strategies for disease characterization carrier detection. J Hered 1999; 90: 112-118.
    CrossrefPubMedSearch in Google Scholar
  • 9 Brooks MJ. Hereditary Coagulopathies. In: Schalm’s Veterinary Hematology. 6th edn. Weiss DJ, Wardrop KJ. Hrsg. Ames: Wiley-Blackwell; 2010: 661-667.
    Search in Google Scholar
  • 10 Brooks MB, Gu W, Ray K. Complete deletion of factor IX gene and inhibition of factor IX activity in a Labrador Retriever with hemophilia B. J Am Vet Med Assoc 1997; 211: 1418-1421.
    PubMedSearch in Google Scholar
  • 11 Brooks MB, Gu W, Barnas JL, Ray J, Ray K. A line 1 insertion in the factor IX gene segregates with mild hemophilia B in dogs. Mamm Genome 2003; 14: 788-795.
    CrossrefPubMedSearch in Google Scholar
  • 12 Brooks MB, MacNguyen R, Hall R, Gupta R, Booth JG. Indirect carrier detection of canine hemophilia A using FVIII microsatellite markers. Anim Genet 2008; 39: 278-283.
    CrossrefPubMedSearch in Google Scholar
  • 13 Buckner RG, Hampton JM, Bird RM, Brock WE. Hemophilia in the Vizsla. J Small Anim Pract 1967; 08: 511-519.
    CrossrefPubMedSearch in Google Scholar
  • 14 Campbell Kl, Greene CE, Dodds WJ. Factor IX deficiency (hemophilia B) in a Scottish terrier. J Am Vet Med Assoc 1983; 15: 170-171.
    PubMedSearch in Google Scholar
  • 15 Dodds WJ. Inherited haemorrghagic defects. In: Current Veterinary Therapy. Vol. VI. Kirk RW. ed. Philadelphia: Saunders; 1977: 438-445.
    Search in Google Scholar
  • 16 Dodds WJ. The diagnosis, management and treatment of bleeding disorders, Part 2. Mod Vet Pract 1977; 58: 756-762.
    PubMedSearch in Google Scholar
  • 17 Dunning MD, Averis GF, Pattinson H, Targett M, Cade S, Herrtage ME. Haemophilia A (factor VIII deficiency) in a litter of Weimaraners. J Small Anim Pract 2009; 50: 357-359.
    CrossrefPubMedSearch in Google Scholar
  • 18 Evans JP, Brinkhous KM, Brayer GD, Reisner HM, High KA. Canine hemophilia B resulting from a point mutation with unusual consequences. Proc Natl Acad Sci USA 1989; 86: 10095-10099.
    CrossrefPubMedSearch in Google Scholar
  • 19 Feldman DG, Brooks MB, Dodds WJ. Hemophilia B (factor IX) deficiency in a family of German shepherd dogs. J Am Vet Med Assoc 1995; 206: 1901-1905.
    PubMedSearch in Google Scholar
  • 20 Fogh JM. A study of hemophilia A in German Shepherd dogs in Denmark. Vet Clin North Am Small Anim Pract 1988; 18: 245-254.
    CrossrefPubMedSearch in Google Scholar
  • 21 Fogh JM, Nygaard L, Andresen E, Nilsson IM. Hemophilia A in dogs, with special reference to hemophilia A among German shepherd dogs in Denmark. I. Pathophysiology, laboratory tests and genetics. Nordisk Vet.-med 1984; 36: 235-240.
    PubMedSearch in Google Scholar
  • 22 Furie B, Furie BC. Molecular basis of hemophilia. Semin Hematol 1990; 27: 270-285.
    PubMedSearch in Google Scholar
  • 23 Gentry PA, Johnstone IB, Sanford SE. Diagnosis of classical hemophilia (hemophilia A) in a standard poodle. Can Vet J 1977; 18: 79-81.
    PubMedSearch in Google Scholar
  • 24 Gerber B, Taboada J, Lothrop Jr CD, Busato A, Hosgood G, Goodman SA, Gaschen FP. Determination of normal values using an automated coagulation timer for activated coagulation time and its application in dogs with hemophilia. J Vet Intern Med 1999; 13: 433-436.
    CrossrefPubMedSearch in Google Scholar
  • 25 Giles AR, Tinlin S, Greenwood R. A canine model of hemophilic (Factor VIII:C deficiency) bleeding. Blood 1982; 60: 727-730.
    PubMedSearch in Google Scholar
  • 26 Giles AR, Tinlin S, Hoogendoorn H, Greenwood P, Greenwood R. Development of factor VIII:C antibodies in dogs with hemophilia A (factor VIII:C deficiency). Blood 1984; 63: 451-456.
    PubMedSearch in Google Scholar
  • 27 Green RA, Lantz GC. Factor VIII deficiency in an Old English Sheepdog. J Am Anim Hosp Assoc 1978; 14: 394-398.
    PubMedSearch in Google Scholar
  • 28 Grøndalen J, Sjaastad Ø, Teige J. Enostosis (panosteitis) in three dogs suffering from hemophilia A. Canine Pract 1991; 16: 10-14.
    PubMedSearch in Google Scholar
  • 29 Gu W, Brooks M, Catalfamo J, Ray J, Ray K. Two distinct mutations cause severe hemophilia B in two unrelated canine pedigrees. Thromb Haemost 1999; 82: 1270-1275.
    Thieme ConnectPubMedSearch in Google Scholar
  • 30 Hoffman M, Monroe DM. A cell-based model of hemostasis. Thromb Haemost 2001; 85: 958-965.
    Thieme ConnectPubMedSearch in Google Scholar
  • 31 Hough C, Kamisue S, Cameron C, Notley C, Tinlin S, Giles A, Lillicrap D. Aberrant splicing and premature termination of transcription of the FVIII gene as a cause of severe canine hemophilia A: similarities with the intron 22 inversion mutation in human hemophilia. Thromb Haemost 2002; 87: 659-665.
    Thieme ConnectPubMedSearch in Google Scholar
  • 32 Hovig T, Dodds WJ, Rowsell HC, Mustard JF. The transformation of hemostatic platelet plugs in normal and factor IX deficient dogs. Am J Pathol 1968; 53: 355-374.
    PubMedSearch in Google Scholar
  • 33 Johnstone IB. Inherited defects of haemostasis. Comp Cont Educ Pract Vet 1982; 04: 483-489.
    PubMedSearch in Google Scholar
  • 34 Johnstone I. Bleeding disorders in dogs: 1. Inherited disorders. In Practice 2002; 98: 2-10.
    PubMedSearch in Google Scholar
  • 35 Johnstone IB, Norris AM. A moderately severe expression of classical hemophilia in a family of German shepherd dogs. Can Vet J 1984; 25: 191-194.
    PubMedSearch in Google Scholar
  • 36 Joseph SA, Brooks MB, Coccari PJ, Riback SC. Hemophilia A in a German shorthair pointer: clinical presentations and diagnosis. J Am Anim Hosp Assoc 1996; 32: 25-28.
    CrossrefPubMedSearch in Google Scholar
  • 37 Kaneko JJ, Cordy DR, Carlson G. Canine hemophilia resembling classic hemophilia A. J Am Vet Med Assoc 1967; 150: 15-21.
    PubMedSearch in Google Scholar
  • 38 Kay MA, Landen CN, Rothenberg SR, Taylor LA, Leland F, Wiehle S, Fang B, Bellinger D, Finegold M, Thompson AR, Read MS, Brinkhous KM, Woo SLC. In vivo hepatic gene therapy: Complete albeit transient correction of factor IX deficiency in hemophilia B dogs. Proc. Natl. Acad. Sci. USA 1994; 91: 2353-2357.
    CrossrefPubMedSearch in Google Scholar
  • 39 Littlewood JD. Haemophilia A (factor VIII deficiency) in German shepherd dogs. J Small Anim Pract 1988; 29: 117-128.
    CrossrefPubMedSearch in Google Scholar
  • 40 Littlewood JD. Inherited bleeding disorders of dogs and cats. J Small Anim Pract 1989; 30: 140-143.
    CrossrefPubMedSearch in Google Scholar
  • 41 Littlewood JD. Haemophilia A. In: Manual of canine and feline haematology and transfusion medicine. Day M, Mackin A, Littlewood J. eds. Quedgeley, Gloucester: British Small Animal Veterinary Association; 2000: 237-241.
    Search in Google Scholar
  • 42 Littlewood JD, Barrowcliffe TW. The development and characterisation of antibodies to human factor VIII in haemophilic dogs. Thromb Haemost 1987; 57: 314-321.
    Thieme ConnectPubMedSearch in Google Scholar
  • 43 Littlewood JD, Matic SE, Smith N. Factor IX deficiency (haemophilia B, Christmas disease) in a cross-bred dog. Vet Rec 1986; 118: 400-401.
    PubMedSearch in Google Scholar
  • 44 Lozier JN, Dutra A, Pak E, Zhou N, Zheng Z, Nichols TC, Bellinger DA, Read M, Morgan RA. The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion. Proc. Natl. Acad. Sci. USA 2002; 99: 12991-12996.
    CrossrefPubMedSearch in Google Scholar
  • 45 Lubas G, Gavazza A, Caldin M. Hemophilia A (factor VIII deficiency) in a family of Belgian Shepherd Malinois dogs bred in Italy. Congress Proceedings of the 21th ECVIM-CA Congress; Sevilla: 08.09.-10.09.2011. S. 253-254. (Poster No. IM-P-16).
  • 46 Lutze G, Kutschmann K, Thomae K, Lutze G, Franke D. Successful treatment of canine haemophilia A with porcine factor VIII. Prakt Tierarzt 1999; 80: 664-670.
    PubMedSearch in Google Scholar
  • 47 Lutze G, Lutze G, Kutschmann K. Hämophilie A und B beim Hund. J Lab Med 2000; 24: 319-324.
    PubMedSearch in Google Scholar
  • 48 Lutze G, Kutschmann K, Lutze Jr G, Lichtenfeld W. Diagnostische Aspekte der Hämophilie B des Hundes. Tierärztl Prax 2000; 28: 369-373.
    PubMedSearch in Google Scholar
  • 49 Mannucci PM. Desmopressin: a nontransfusional form of treatment for congenital and acquired bleeding disorders. Blood 1988; 72: 1449-1455.
    PubMedSearch in Google Scholar
  • 50 Mansell PD, Parry BW. Stability of canine factor VIII activity and von Willebrand factor antigen concentration in vitro. Res Vet Sci 1991; 51: 313-316.
    CrossrefPubMedSearch in Google Scholar
  • 51 Mansell PD, Parry BW. Changes in factor VIII: coagulant activity and von Willebrand factor antigen concentration after subcutaneous injection of desmopressin in dogs with mild hemophilia A. J Vet Int Med 1991; 05: 191-194.
    CrossrefPubMedSearch in Google Scholar
  • 52 Mansell PD, Parry BW. Carrier detection in human and canine hemophilia A. Vet Bulletin 1992; 62: 999-1007.
    PubMedSearch in Google Scholar
  • 53 Mansell PD, Parry BW. Changes in factor VIII activity and von Willebrand factor antigen concentration with age in dogs. Br Vet J 1992; 148: 329-337.
    CrossrefPubMedSearch in Google Scholar
  • 54 Mansell PD, Parry BW. Effect of acepromacine, xylazine and thiopentone on factor VIII activity and von Willebrand factor antigen concentration in dogs. Aust Vet J 1992; 69: 187-190.
    CrossrefPubMedSearch in Google Scholar
  • 55 Mansell PD, Parry BW, van Orsouw PJ. Haemophilia A in a family of miniature poodles. Aust Vet J 1990; 67: 420-421.
    CrossrefPubMedSearch in Google Scholar
  • 56 Mansell PD, Parry BW, Anderson GA. Detection of canine carriers of haemophilia A using factor VIII activity and von Willebrand factor antigen concentration. Prev Vet Med 1993; 16: 133-139.
    CrossrefPubMedSearch in Google Scholar
  • 57 Mauser AE, Whitlark J, Whitney KM, Lothrop CD. A deletion mutation causes hemophilia B in Lhasa apso dogs. Blood 1996; 88: 3451-3455.
    PubMedSearch in Google Scholar
  • 58 Mertens K, Briët E, Giles AR. The role of factor VII in haemostasis: infusion studies of factor VIIa in a canine model of factor VIII deficiency. Thromb Haemost 1990; 64: 138-144.
    Thieme ConnectPubMedSearch in Google Scholar
  • 59 Mischke R. Vergleich der Faktor-VIII:C- und Faktor-IX-Empfindlichkeit verschiedener kommerzieller APTT-Reagenzien für canines Plasma. Berl Münch Tierärztl Wschr 1999; 112: 394-399.
    PubMedSearch in Google Scholar
  • 60 Mischke R. Influence of factor VIII:C and factor IX activity in plasma of haemophilic dogs on the activated partial thromboplastin time measured with two commercial reagents. Haemophilia 2000; 06: 135-139.
    CrossrefPubMedSearch in Google Scholar
  • 61 Mischke R, Rivera PARamirez, Deniz A, Hänies R, Otto K. Hämophilie A beim Hund: Symptome, Blutgerinnungsanalyse und Behandlung. Berl Münch Tierärztl Wochenschr 1996; 109: 279-287.
    PubMedSearch in Google Scholar
  • 62 Mischke R, Hänies R, Deniz A, Hart S. Hämophilie B bei einem Mischlings-Rüden: Behandlung einer Blutungskrise mit frisch-gefrorenem Plasma. Dtsch Tierärztl Wochenschr 1996; 103: 3-6.
    PubMedSearch in Google Scholar
  • 63 Mischke R, Kühnlein P, Kehl A, Langbein-Detsch I, Steudle F, Schmid A, Dandekar T, Czwalinna A, Müller E. G244E in the canine factor IX gene leads to severe haemophilia B in Rhodesian Ridgebacks. Vet J 2011; 187: 113-118.
    CrossrefPubMedSearch in Google Scholar
  • 64 Mischke R, Wilhelm C, Czwalinna A, Varvenne M, Narten K, von Depka M. Canine haemophilia A caused by a mutation leading to a stop codon. Vet Rec 2011; 169: 496 doi: 10.1136/vr.d4677..
    PubMedSearch in Google Scholar
  • 65 Mischke R, Kühnlein P, Kehl A, Jahn M, Ertl R, Klein D, Cecil A, Dandekar T, Müller E. Genetic analysis of haemophilic Havanese dogs. Proceedings of the 13th Conference of the ESVCP/ECVCP; Dublin: 31.08.-03.09.2011c. S. 30 (Abstr. 46).
  • 66 Murtaugh RJ, Dodds WJ. Hemophilia A in a female dog. J Am Vet Med Assoc 1988; 193: 351-352.
    PubMedSearch in Google Scholar
  • 67 Nakata M, Sakai M, Sakai T. Hemophilia B in a crossbred Maltese dog. J Vet Med Sci 2006; 68: 1223-1224.
    CrossrefPubMedSearch in Google Scholar
  • 68 Nichols TC, Raymer RA, Franck HWG, Merricks EP, Bellinger DA, Defriess N, Margaritis P, Arruda VR, Kay MA, High KA. Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B. Haemophilia 2010; 16: 19-23.
    CrossrefPubMedSearch in Google Scholar
  • 69 Niemeyer GP, Herzog RW, Mount J, Arruda VR, Tillson DM, Hathcock J, van Ginkel FW, High KA, Lothrop Jr CD. Long-term correction of inhibitorprone hemophilia B dogs treated with liver-directed AAV2-mediated factor IX gene therapy. Blood 2009; 113: 797-806.
    CrossrefPubMedSearch in Google Scholar
  • 70 Okin R, Dodds WJ. Canine Haemophilia A and B. Canine Pract 1980; 07: 61-68.
    PubMedSearch in Google Scholar
  • 71 Parry BW, Holloway SA, Birch DJ, Mackin AJ. Haemophilia A in a cocker spaniel dog. Aust Vet J 1988; 65: 326-327.
    CrossrefPubMedSearch in Google Scholar
  • 72 Parry BW, Howard MA, Mansell PD, Holloway SA. Haemophilia A in German shepherd dogs. Aust Vet J 1988; 65: 276-279.
    CrossrefPubMedSearch in Google Scholar
  • 73 Pearce RD, Copper ML. Haemophilia A in the cocker spaniel: a case report. J Small Anim Pract 1983; 24: 515-523.
    CrossrefPubMedSearch in Google Scholar
  • 74 Peterson ME, Dodds WJ. Factor IX deficiency in an Alaskan Malamute. J Am Vet Med Assoc 1979; 174: 1326-1327.
    PubMedSearch in Google Scholar
  • 75 Pijnappels MIM, Briet E, Van Der Zwet GT, Huisden R, Van Tilburg NH, Eulderink F. Evaluation of the cuticle bleeding time in canine haemophilia A. Thromb Haemost 1986; 55: 70-73.
    Thieme ConnectPubMedSearch in Google Scholar
  • 76 Sherding RG, DiBartola SP. Hemophilia B (factor IX deficiency) in an old English Sheepdog. J Am Vet Med Assoc 1980; 176: 141-142.
    PubMedSearch in Google Scholar
  • 77 Slappendel RJ. Hemophilia A and hemophilia B in a family of French bulldogs. Tijdschr Diergeneeskd 1975; 100: 1075-1088.
    PubMedSearch in Google Scholar
  • 78 Smith SA. The cell-based model of coagulation. J Vet Emerg Crit Care 2009; 19: 3-10.
    CrossrefPubMedSearch in Google Scholar
  • 79 Spurling NW. Hereditary disorders of haemostasis in dogs: A critical review of the literature. Vet Bull 1980; 50: 151-173.
    PubMedSearch in Google Scholar
  • 80 Stokol T, Trepanier L, Parry BW, Finnin BC. Pharmacokinetics of von Willebrand factor and factor VIII in canine von Willebrand disease and haemophilia A. Res Vet Sci 1997; 63: 23-27.
    CrossrefPubMedSearch in Google Scholar
  • 81 Stokol T, Parry B. Efficacy of fresh-frozen plasma and cryoprecipitate in dogs with von Willebrand’s disease or hemophilia A. J Vet Int Med 1998; 12: 84-92.
    CrossrefPubMedSearch in Google Scholar
  • 82 Van der Velden P, Giles AR. A detailed morphological evaluation of the evolution of the haemostatic plug in normal, factor VII and factor VIII deficient dogs. Br J Haematol 1988; 70: 345-355.
    CrossrefPubMedSearch in Google Scholar
  • 83 Verlander JW, Gorman NT, Dodds WJ. Factor IX deficiency (hemophilia B) in a litter of Labrador retrievers. J Am Vet Med Assoc 1984; 185: 83-84.
    PubMedSearch in Google Scholar