OMIA:000437-9615 : Haemophilia A in Canis lupus familiaris (dog)

In other species: crab-eating macaque , domestic cat , horse , pig , taurine cattle , sheep

Categories: Haematopoietic system phene

Links to possible relevant human trait(s) and/or gene(s) in OMIM: 306700 (trait) , 300841 (gene)

Links to relevant human diseases in MONDO:

Mendelian trait/disorder: yes

Mode of inheritance: X-linked recessive

Considered a defect: yes

Key variant known: yes

Year key variant first reported: 2002

Cross-species summary: Also called factor VIII deficiency. Impaired coagulability of the blood, with a consequential strong tendency to bleed, due to a deficiency of clotting factor VIII. Since the gene for this factor is located on the X chromosome, the disorder is expected to be X-linked. As with haemophilia B, this expectation has been confirmed in all species of mammal in which the disorder has been reported. In humans, there are hundreds of different mutations that give rise to haemophilia A. In domesticated animals, the disorder has been reported in a large range of species.

Species-specific name: classical haemophilia/hemophilia

Species-specific description: The historical section of this entry is based on information in the review by Lozier and Nichols (2013). Some missing references were also gleaned from this review. FN is grateful to the authors for their very useful review.

History: A colonly of Irish Setters in which this disorder segregates was established in 1947 at the University of North Carolina at Chapel Hill, by Kenneth M. Brinkhous. It was first described by Graham et al. (1949) and Brinkhous and Graham (1950). A Miniature Schnauzer colony was established at Queens University, Toronto, in 1980 (Giles et al., 1982).

Molecular basis: By cloning and sequencing a very likely comparative candidate gene (based on the homologous human disorder), a likely causal mutation in the canine factor 8 gene (F8) was discovered: in the Queens University Miniature Schnauzer colony, an intronic inversion that results in "aberrant splicing and premature termination of transcription of the FVIII gene, resulting in a polyadenylated transcript lacking exons distal to 22 and terminating with a novel sequence element (NSE)" (Hough et al., 2002); and (a few months later) in the Chapel Hill Irish Setter colony, the same intron-22 inversion (Lozier et al., 2002). This inversion is very similar to a causal mutation in the human F8 gene. In an affected male German Shepherd dog, Mischke et al. (2011) reported a nonsense mutation in the F8 gene, namely a "single-base exchange at nucleotide position 98 (TGG>TAG) was detected resulting in a STOP codon (Trp33Stop) in frame". Two additional causal mutations were reported by Christopherson et al. (2014): c.1412C>G, P471R in exon 10 in a Boxer, and c.1643G>A, p.C548Y in exon 11 in a German Shepherd dog. Lozier et al. (2016) reported a male Old English Sheep Dog with severe haemophilia A, apparently due to a novel variant, namely "a C→T transition in exon 12 of the factor VIII gene [c.1786C>T] that created a premature stop codon at amino acid 577 in the A2 domain of the protein [p.Arg577Stop] . . . [which] is analogous to the previously described human factor VIII mutation at Arg583, which likewise is a CpG dinucleotide transition causing a premature stop codon in exon 12". Kehl et al. (2021) reported "a short interspersed nuclear element (SINE) insertion in exon 14 of the F8 gene" as the likely causal variant in two affected "related male Rhodesian Ridgebacks". Hytönen et al. (2023) investigated "hemophilia A in two distinct Labrador Retriever (LR) pedigrees. Whole-genome sequencing on an affected dog from litter 1 identified a case-specific frameshift deletion variant in F8 predicted to cause a premature stop codon (c.2923_2924del, p.(E975Kfs*8)). This variant was hemizygous in all the affected males from litter 1 (n = 3), while all the unaffected LRs in the pedigree were heterozygous or wild-type (n = 22). Additionally, screened samples from 199 LRs were all found to be wild-type. ... However, it is important to note that the affected LR with decreased FVIII activity from litter 2 was wild-type for the identified deletion variant, and no segregating F8 variants were detected when this dog's DNA sample was whole-genome sequenced." After diagnosing factor VIII deficiency in a Border Collie male pup whose two litter-brothers had been euthanased due to "acute hematoma formation", and subsequently sequencing the F8 genes in the surviving pup and its dam, Brockmann et al. (2023) discovered "a deletion in exon 14 of the F8 gene. This c.3206delA variant leads to a frameshift in amino acid sequence and a premature stop codon (p.Asn1069IlefsTer7). The detection of the mutation and consequent testing of related dogs revealed that the deletion most likely had occurred spontaneously in the mother and had been transmitted to several of her offspring in different litters."

Clinical features: Dogs with haemophilia A present with spontaneous bleeding, including bleeding in soft tissue, joints (causing lameness) and body cavities. Excessive bleeding is reported after tooth extraction or after deciduous teeth are lost and after surgery (Mischke et al., 1996; Nichols et al., 2010). Coagulation analysis will show a markedly prolonged activated partial thromboplastin time (APTT) with a low factor VIII activity (Gavazza et al., 2014; Nishitani and Kitoh, 2021). Severity of clinical presentation varies between breeds. IT thanks DVM student Yi Fei Choong, who provided the basis of this contribution in May 2023.

Breeds: Belgian Shepherd Dog, Malinois (Dog) (VBO_0200147), Border Collie (Dog) (VBO_0200193), Boxer (Dog) (VBO_0200210), Cocker Spaniel (Dog) (VBO_0200372), German Shepherd Dog (Dog) (VBO_0200577), German Shorthaired Pointer (Dog) (VBO_0200583), Golden Retriever (Dog) (VBO_0200610), Irish Setter (Dog) (VBO_0200702), Labrador Retriever (Dog) (VBO_0200800), Miniature Schnauzer (Dog) (VBO_0200896), Old English Sheepdog (Dog) (VBO_0200969), Poodle (Dog) (VBO_0201048), Rhodesian Ridgeback (Dog) (VBO_0201135), Siberian Husky (Dog) (VBO_0201233), Weimaraner (Dog) (VBO_0201401).
Breeds in which the phene has been documented. (If a likely causal variant has been documented for the phene, see the variant table breeds in which the variant has been reported).

Associated gene:

Symbol Description Species Chr Location OMIA gene details page Other Links
F8 coagulation factor VIII, procoagulant component Canis lupus familiaris X NC_051843.1 (126170925..126024520) F8 Homologene, Ensembl , NCBI gene


By default, variants are sorted chronologically by year of publication, to provide a historical perspective. Readers can re-sort on any column by clicking on the column header. Click it again to sort in a descending order. To create a multiple-field sort, hold down Shift while clicking on the second, third etc relevant column headers.

WARNING! Inclusion of a variant in this table does not automatically mean that it should be used for DNA testing. Anyone contemplating the use of any of these variants for DNA testing should examine critically the relevant evidence (especially in breeds other than the breed in which the variant was first described). If it is decided to proceed, the location and orientation of the variant sequence should be checked very carefully.

Since October 2021, OMIA includes a semiautomated lift-over pipeline to facilitate updates of genomic positions to a recent reference genome position. These changes to genomic positions are not always reflected in the ‘acknowledgements’ or ‘verbal description’ fields in this table.

OMIA Variant ID Breed(s) Variant Phenotype Gene Allele Type of Variant Source of Genetic Variant Reference Sequence Chr. g. or m. c. or n. p. Verbal Description EVA ID Year Published PubMed ID(s) Acknowledgements
363 Irish Setter (Dog) Miniature Schnauzer (Dog) Haemophilia A F8 splicing Naturally occurring variant X intronic inversion that results in "aberrant splicing and premature termination" 2002 12008949
1655 Border Collie (Dog) Haemophilia A F8 deletion, small (<=20) Naturally occurring variant CanFam3.1 X g.122956942delA c.3206delA NM_001003212.1 2023 38104983
350 Old English Sheepdog (Dog) Haemophilia A F8 nonsense (stop-gain) Naturally occurring variant CanFam3.1 X g.122973422G>A c.1786C>T p.(R596*) 2016 27780008 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
100 German Shepherd Dog (Dog) Haemophilia A F8 missense Naturally occurring variant CanFam3.1 X g.122975611C>T c.1700G>A p.(C567Y) NM_001003212.1; NP_001003212.1; published as c.1643G>A & p.(C548Y); coordinates in the table have been updated to a recent reference genome and / or transcript. 2014 25040606
99 Boxer (Dog) Haemophilia A F8 missense Naturally occurring variant CanFam3.1 X g.122981181G>C c.1469C>G p.(P490R) NM_001003212.1; NP_001003212.1; published as c.1412C>G & p.(P471R); coordinates in the table have been updated to a recent reference genome and/ or transcript 2014 25040606
272 German Shepherd Dog (Dog) Haemophilia A F8 nonsense (stop-gain) Naturally occurring variant CanFam3.1 X g.123043081C>T c.98G>A p.(W33*) 2011 21949058 Variant coordinates obtained from or confirmed by EBI's Some Effect Predictor (VEP) tool
1284 Rhodesian Ridgeback (Dog) Haemophilia A F8 insertion, gross (>20) Naturally occurring variant UU_Cfam_GSD_1.0 X g.124073876_124073877insN[221] c.4824_4825insN[221] NM_001003212.1; published as c.4824_25ins221, genomic coordinates published as chrX: 1240738676_77. After review of the position in the reference genome on the 17/7/2023 the genomic coordinates have been updated to g.124073876_124073877insN[221] in this table. 2021 33494213
1588 Labrador Retriever (Dog) Haemophilia A F8 deletion, small (<=20) Naturally occurring variant UU_Cfam_GSD_1.0 X g.124075777_124075778del c.2923_2924del p.(E975Kfs*8) NM_001003212.1; NP_001003212 2023 37438956

Cite this entry

Nicholas, F. W., Tammen, I., & Sydney Informatics Hub. (2023). OMIA:000437-9615: Online Mendelian Inheritance in Animals (OMIA) [dataset].


Note: the references are listed in reverse chronological order (from the most recent year to the earliest year), and alphabetically by first author within a year.

2024 Batty, P., Fong, S., Franco, M., Sihn, C.R., Swystun, L.L., Afzal, S., Harpell, L.M., Hurlbut, D., Pender, A., Su, C., Thomsen, H., Wilson, C., Youssar, L., Winterborn, A., Gil-Farina, I., Lillicrap, D. :
Vector integration and fate in the hemophilia dog liver multi-years following AAV-FVIII gene transfer. Blood 143:2373-2385, 2024. Pubmed reference: 38452208. DOI: 10.1182/blood.2023022589.
Doshi, B.S., Samelson-Jones, B.J., Nichols, T.C., Merricks, E.P., Siner, J.L., French, R.A., Lee, B.J., Arruda, V.R., Callan, M.B. :
AAV gene therapy in companion dogs with severe hemophilia: Real-world long-term data on immunogenicity, efficacy, and quality of life. Mol Ther Methods Clin Dev 32:101205, 2024. Pubmed reference: 38374963. DOI: 10.1016/j.omtm.2024.101205.
Strilchuk, A.W., Hur, W.S., Batty, P., Sang, Y., Abrahams, S.R., Yong, A.S.M., Leung, J., Silva, L.M., Schroeder, J.A., Nesbitt, K., de Laat, B., Moutsopoulos, N.M., Bugge, T.H., Shi, Q., Cullis, P.R., Merricks, E.P., Wolberg, A.S., Flick, M.J., Lillicrap, D., Nichols, T.C., Kastrup, C.J. :
Lipid nanoparticles and siRNA targeting plasminogen provide lasting inhibition of fibrinolysis in mouse and dog models of hemophilia A. Sci Transl Med 16:eadh0027, 2024. Pubmed reference: 38381848. DOI: 10.1126/scitranslmed.adh0027.
2023 Brockmann, M., Mensing, N., von Luckner, J., Müller, E., Kehl, A. :
Hemophilia A in a litter of Border Collies caused by a one base pair deletion in the F8 gene. Vet Clin Pathol 52:607-612, 2023. Pubmed reference: 38104983. DOI: 10.1111/vcp.13312.
Hytönen, M.K., Viitanen, S., Hundi, S., Donner, J., Lohi, H., Kaukonen, M. :
A frameshift deletion in F8 associated with hemophilia A in Labrador Retriever dogs. Anim Genet 54:606-612, 2023. Pubmed reference: 37438956. DOI: 10.1111/age.13345.
Van Gorder, L., Doshi, B.S., Willis, E., Nichols, T.C., Cook, E., Everett, J.K., Merricks, E.P., Arruda, V.R., Bushman, F.D., Callan, M.B., Samelson-Jones, B.J. :
Analysis of vector genome integrations in multicentric lymphoma after AAV gene therapy in a severe hemophilia A dog. Mol Ther Methods Clin Dev 31:101159, 2023. Pubmed reference: 38094200. DOI: 10.1016/j.omtm.2023.101159.
West, N., Butterfield, S., Rusbridge, C., Fernandez, A., Tabanez, J., Rudolf, N.J., Archer, S., Whittaker, D. :
Non-traumatic hemorrhagic myelopathy in dogs. J Vet Intern Med 37:1129-1138, 2023. Pubmed reference: 37095733. DOI: 10.1111/jvim.16694.
2022 Lubbers, C., Beukers, M., Bergknut, N., Paes, G. :
Hemophilia a resulting in severe hyperesthesia due to extraparenchymal spinal cord hemorrhage in a young Golden Retriever puppy. Vet Sci 9:638, 2022. Pubmed reference: 36423087. DOI: 10.3390/vetsci9110638.
2021 Arruda, V.R., Weber, J., Samelson-Jones, B.J. :
Gene therapy for inherited bleeding disorders. Semin Thromb Hemost 47:161-173, 2021. Pubmed reference: 33636747. DOI: 10.1055/s-0041-1722862.
Kehl, A., Haaland, A.H., Langbein-Detsch, I., Mueller, E. :
A SINE insertion in F8 gene leads to severe form of hemophilia A in a family of Rhodesian Ridgebacks. Genes (Basel) 12:134, 2021. Pubmed reference: 33494213. DOI: 10.3390/genes12020134.
Nishitani, Y., Kitoh, K. :
Haemophilia A in a female mixed-breed dog. J Small Anim Pract 62:496-499, 2021. Pubmed reference: 32716072. DOI: 10.1111/jsap.13198.
Noda, M., Tatsumi, K., Matsui, H., Matsunari, Y., Sato, T., Fukuoka, Y., Hotta, A., Okano, T., Kichikawa, K., Sugimoto, M., Shima, M., Nishio, K. :
Development of alternative gene transfer techniques for ex vivo and in vivo gene therapy in a canine model. Regen Ther 18:347-354, 2021. Pubmed reference: 34584911. DOI: 10.1016/j.reth.2021.08.009.
2020 Switonski, M. :
Impact of gene therapy for canine monogenic diseases on the progress of preclinical studies. J Appl Genet 61:179-186, 2020. Pubmed reference: 32189222. DOI: 10.1007/s13353-020-00554-8.
2018 Sun, J., Shao, W., Chen, X., Merricks, E.P., Wimsey, L., Abajas, Y.L., Niemeyer, G.P., Lothrop, C.D., Monahan, P.E., Samulski, R.J., Nichols, T.C., Li, C. :
An observational study from long-term AAV re-administration in two hemophilia dogs. Mol Ther Methods Clin Dev 10:257-267, 2018. Pubmed reference: 30140713. DOI: 10.1016/j.omtm.2018.07.011.
2017 Decambron, A., Manassero, M., Thibaud, J.L., Reyes-Gomez, E., Viateau, V. :
Bone haemophilic pseudotumour of the ulna: A rare complication of haemophilia in a dog. Vet Comp Orthop Traumatol 30:371-376, 2017. Pubmed reference: 28763522. DOI: 10.3415/VCOT-17-01-0002.
2016 Callan, M.B., Haskins, M.E., Wang, P., Zhou, S., High, K.A., Arruda, V.R. :
Successful phenotype improvement following gene therapy for severe hemophilia A in privately owned dogs. PLoS One 11:e0151800, 2016. Pubmed reference: 27011017. DOI: 10.1371/journal.pone.0151800.
Lozier, J.N., Kloos, M.T., Merricks, E.P., Lemoine, N., Whitford, M.H., Raymer, R.A., Bellinger, D.A., Nichols, T.C. :
Severe hemophilia A in a male Old English Sheep Dog with a C→T transition that created a premature stop codon in factor VIII. Comp Med 66:405-411, 2016. Pubmed reference: 27780008.
Nichols, T.C., Hough, C., Agersø, H., Ezban, M., Lillicrap, D. :
Canine models of inherited bleeding disorders in the development of coagulation assays, novel protein replacement and gene therapies. J Thromb Haemost 14:894-905, 2016. Pubmed reference: 26924758. DOI: 10.1111/jth.13301.
Wang, Q., Dong, B., Firrman, J., Wu, W., Roberts, S., Moore, A.R., Liu, L.S., Chin, M.P., Diao, Y., Kost, J., Xiao, W. :
Evaluation of the biological differences of canine and human factor VIII in gene delivery: Implications in human hemophilia treatment. Gene Ther 23:597-605, 2016. Pubmed reference: 27064790. DOI: 10.1038/gt.2016.34.
Yen, C.T., Fan, M.N., Yang, Y.L., Chou, S.C., Yu, I.S., Lin, S.W. :
Current animal models of hemophilia: the state of the art. Thromb J 14:22, 2016. Pubmed reference: 27766048. DOI: 10.1186/s12959-016-0106-0.
2015 Dolgin, E. :
Oral solutions. Sci Am 312:S12-3, 2015. Pubmed reference: 25597119. DOI: 10.1038/scientificamerican0115-s12.
Sohn, E. :
Dogged pursuit. Sci Am 312:S18-9, 2015. Pubmed reference: 25597122. DOI: 10.1038/scientificamerican0115-s18.
2014 Aslanian, M.E., Sharp, C.R., Rozanski, E.A., de Laforcade, A.M., Rishniw, M., Brooks, M.B. :
Clinical outcome after diagnosis of hemophilia A in dogs. J Am Vet Med Assoc 245:677-83, 2014. Pubmed reference: 25181272. DOI: 10.2460/javma.245.6.677.
Christopherson, P.W., Bacek, L.M., King, K.B., Boudreaux, M.K. :
Two novel missense mutations associated with hemophilia A in a family of Boxers, and a German Shepherd dog. Vet Clin Pathol 43:312-6, 2014. Pubmed reference: 25040606. DOI: 10.1111/vcp.12172.
Gavazza, A., Lubas, G., Trotta, M., Caldin, M. :
Hemophilia A in a Belgian Shepherd Malinois dog: case report. Res Vet Sci 97:96-8, 2014. Pubmed reference: 24952680. DOI: 10.1016/j.rvsc.2014.05.007.
Ozelo, M.C., Vidal, B., Brown, C., Notley, C., Hegadorn, C., Webster, S., Harpell, L., Ahlin, J., Winterborn, A., Handforth, J., Arruda, V.R., Hough, C., Lillicrap, D. :
Omental implantation of endothelial progenitor cells in hemophilia dogs results in long-term circulating FVIII antigen and a complex immune response. Blood 123:4045-53, 2014. Pubmed reference: 24829206. DOI: 10.1182/blood-2013-12-545780.
2013 Du, L.M., Nurden, P., Nurden, A.T., Nichols, T.C., Bellinger, D.A., Jensen, E.S., Haberichter, S.L., Merricks, E., Raymer, R.A., Fang, J., Koukouritaki, S.B., Jacobi, P.M., Hawkins, T.B., Cornetta, K., Shi, Q., Wilcox, D.A. :
Platelet-targeted gene therapy with human factor VIII establishes haemostasis in dogs with haemophilia A. Nat Commun 4:2773, 2013. Pubmed reference: 24253479. DOI: 10.1038/ncomms3773.
Lozier, J.N., Nichols, T.C. :
Animal models of hemophilia and related bleeding disorders. Semin Hematol 50:175-184, 2013. Pubmed reference: 23956467. DOI: 10.1053/j.seminhematol.2013.03.023.
2012 Agersø, H., Stennicke, H.R., Pelzer, H., Olsen, E.N., Merricks, E.P., Defriess, N.A., Nichols, T.C., Ezban, M. :
Pharmacokinetics and pharmacodynamics of turoctocog alfa and N8-GP in haemophilia A dogs. Haemophilia 18:941-7, 2012. Pubmed reference: 22812621. DOI: 10.1111/j.1365-2516.2012.02896.x.
Barr, J.W., McMichael, M. :
Inherited disorders of hemostasis in dogs and cats. Top Companion Anim Med 27:53-8, 2012. Pubmed reference: 23031456. DOI: 10.1053/j.tcam.2012.07.006.
Dumont, J.A., Liu, T., Low, S.C., Zhang, X., Kamphaus, G., Sakorafas, P., Fraley, C., Drager, D., Reidy, T., McCue, J., Franck, H.W., Merricks, E.P., Nichols, T.C., Bitonti, A.J., Pierce, G.F., Jiang, H. :
Prolonged activity of a recombinant factor VIII-Fc fusion protein in hemophilia A mice and dogs. Blood 119:3024-30, 2012. Pubmed reference: 22246033. DOI: 10.1182/blood-2011-08-367813.
Mischke, R. :
[Haemophilia A and B in dogs]. Tierarztl Prax Ausg K Kleintiere Heimtiere 40:44-53; quiz 54, 2012. Pubmed reference: 22331328.
Sabatino, D.E., Nichols, T.C., Merricks, E., Bellinger, D.A., Herzog, R.W., Monahan, P.E. :
Animal models of hemophilia. Prog Mol Biol Transl Sci 105:151-209, 2012. Pubmed reference: 22137432. DOI: 10.1016/B978-0-12-394596-9.00006-8.
2011 Karpf, D.M., Kjalke, M., Thim, L., Agersø, H., Merricks, E.P., Defriess, N., Nichols, T.C., Ezban, M. :
Pharmacokinetics and ex vivo whole blood clot formation of a new recombinant FVIII (N8) in haemophilia A dogs. Haemophilia 17:e963-8, 2011. Pubmed reference: 21682818. DOI: 10.1111/j.1365-2516.2011.02580.x.
Knudsen, T., Kristensen, A.T., Nichols, T.C., Agersø, H., Jensen, A.L., Kjalke, M., Ezban, M., Tranholm, M. :
Pharmacokinetics, pharmacodynamics and safety of recombinant canine FVIIa in a study dosing one haemophilia A and one haemostatically normal dog. Haemophilia 17:962-70, 2011. Pubmed reference: 21645178. DOI: 10.1111/j.1365-2516.2011.02536.x.
Mischke, R., Wilhelm, C.h., Czwalinna, A., Varvenne, M., Narten, K., von Depka, M. :
Canine haemophilia A caused by a mutation leading to a stop codon. Vet Rec 169:496b, 2011. Pubmed reference: 21949058. DOI: 10.1136/vr.d4677.
Petersen, L.C., Karpf, D.M., Agersø, H., Hermit, M.B., Pelzer, H., Persson, E., Nichols, T.C., Ezban, M. :
Intravascular inhibition of factor VIIa and the analogue NN1731 by antithrombin. Br J Haematol 152:99-107, 2011. Pubmed reference: 21083658. DOI: 10.1111/j.1365-2141.2010.08432.x.
2010 Finn, J.D., Ozelo, M.C., Sabatino, D.E., Franck, H.W., Merricks, E.P., Crudele, J.M., Zhou, S., Kazazian, H.H., Lillicrap, D., Nichols, T.C., Arruda, V.R. :
Eradication of neutralizing antibodies to factor VIII in canine hemophilia A after liver gene therapy. Blood 116:5842-8, 2010. Pubmed reference: 20876851. DOI: 10.1182/blood-2010-06-288001.
Nichols, T.C., Raymer, R.A., Franck, H.W., Merricks, E.P., Bellinger, D.A., DeFriess, N., Margaritis, P., Arruda, V.R., Kay, M.A., High, K.A. :
Prevention of spontaneous bleeding in dogs with haemophilia A and haemophilia B. Haemophilia 16 Suppl 3:19-23, 2010. Pubmed reference: 20586797. DOI: 10.1111/j.1365-2516.2010.02255.x.
Othman, M., Powell, S., Hopman, W.M., Lillicrap, D. :
Variability of thromboelastographic responses following the administration of rFVIIa to haemophilia A dogs supports the individualization of therapy with a global test of haemostasis. Haemophilia 16:919-25, 2010. Pubmed reference: 20609015. DOI: 10.1111/j.1365-2516.2010.02336.x.
2009 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 50:357-359, 2009. Pubmed reference: 19508492. DOI: 10.1111/j.1748-5827.2009.00727.x.
Margaritis, P., Roy, E., Aljamali, M.N., Downey, H.D., Giger, U., Zhou, S., Merricks, E., Dillow, A., Ezban, M., Nichols, T.C., High, K.A. :
Successful treatment of canine hemophilia by continuous expression of canine FVIIa. Blood 113:3682-9, 2009. Pubmed reference: 19109232. DOI: 10.1182/blood-2008-07-168377.
Milbauer, L.C., Enenstein, J.A., Roney, M., Solovey, A., Bodempudi, V., Nichols, T.C., Hebbel, R.P. :
Blood outgrowth endothelial cell migration and trapping in vivo: a window into gene therapy. Transl Res 153:179-89, 2009. Pubmed reference: 19304277. DOI: 10.1016/j.trsl.2008.12.009.
Nichols, TC., Dillow, AM., Franck, HW., Merricks, EP., Raymer, RA., Bellinger, DA., Arruda, VR., High, KA. :
Protein replacement therapy and gene transfer in canine models of hemophilia A, hemophilia B, von willebrand disease, and factor VII deficiency. ILAR J 50:144-67, 2009. Pubmed reference: 19293459.
Sabatino, D.E., Freguia, C.F., Toso, R., Santos, A., Merricks, E.P., Kazazian, H.H., Nichols, T.C., Camire, R.M., Arruda, V.R. :
Recombinant canine B-domain-deleted FVIII exhibits high specific activity and is safe in the canine hemophilia A model. Blood 114:4562-5, 2009. Pubmed reference: 19770361. DOI: 10.1182/blood-2009-05-220327.
2008 Brooks, M.B., MacNguyen, R., Hall, R., Gupta, R., Booth, J.G. :
Indirect carrier detection of canine haemophilia A using factor VIII microsatellite markers. Anim Genet 39:278-83, 2008. Pubmed reference: 18454805. DOI: 10.1111/j.1365-2052.2008.01726.x.
Prasad, S., Lillicrap, D., Labelle, A., Knappe, S., Keller, T., Burnett, E., Powell, S., Johnson, K.W. :
Efficacy and safety of a new-class hemostatic drug candidate, AV513, in dogs with hemophilia A. Blood 111:672-9, 2008. Pubmed reference: 17978172. DOI: 10.1182/blood-2007-07-098913.
2006 Arruda, V.R. :
Toward gene therapy for hemophilia A with novel adenoviral vectors: successes and limitations in canine models. J Thromb Haemost 4:1215-7, 2006. Pubmed reference: 16706962. DOI: 10.1111/j.1538-7836.2006.01964.x.
Jiang, H., Lillicrap, D., Patarroyo-White, S., Liu, T., Qian, X., Scallan, C.D., Powell, S., Keller, T., McMurray, M., Labelle, A., Nagy, D., Vargas, J.A., Zhou, S., Couto, L.B., Pierce, G.F. :
Multiyear therapeutic benefit of AAV serotypes 2, 6, and 8 delivering factor VIII to hemophilia A mice and dogs. Blood 108:107-15, 2006. Pubmed reference: 16522813. DOI: 10.1182/blood-2005-12-5115.
McCormack, W.M., Seiler, M.P., Bertin, T.K., Ubhayakar, K., Palmer, D.J., Ng, P., Nichols, T.C., Lee, B. :
Helper-dependent adenoviral gene therapy mediates long-term correction of the clotting defect in the canine hemophilia A model. J Thromb Haemost 4:1218-25, 2006. Pubmed reference: 16706963. DOI: 10.1111/j.1538-7836.2006.01901.x.
Sarkar, R., Mucci, M., Addya, S., Tetreault, R., Bellinger, D.A., Nichols, T.C., Kazazian, H.H. :
Long-term efficacy of adeno-associated virus serotypes 8 and 9 in hemophilia a dogs and mice. Hum Gene Ther 17:427-39, 2006. Pubmed reference: 16610930. DOI: 10.1089/hum.2006.17.427.
2005 Brooks, MB., Barnas, JL., Fremont, J., Ray, J. :
Cosegregation of a factor VIII microsatellite marker with mild hemophilia A in Golden Retriever dogs. J Vet Intern Med 19:205-10, 2005. Pubmed reference: 15822565.
Ko, S., Tanaka, I., Kanokogi, H., Kanehiro, H., Okayama, J., Ori, J., Shima, M., Yoshioka, A., Giles, A., Nakajima, Y. :
Efficacy of auxiliary partial orthotopic liver transplantation for cure of hemophilia in a canine hemophilia A model. Transplant Proc 37:1131-3, 2005. Pubmed reference: 15848646. DOI: 10.1016/j.transproceed.2005.01.003.
Xu, L., Nichols, T.C., Sarkar, R., McCorquodale, S., Bellinger, D.A., Ponder, K.P. :
Absence of a desmopressin response after therapeutic expression of factor VIII in hemophilia A dogs with liver-directed neonatal gene therapy. Proc Natl Acad Sci U S A 102:6080-5, 2005. Pubmed reference: 15837921. DOI: 10.1073/pnas.0409249102.
2004 Brown, B.D., Shi, C.X., Powell, S., Hurlbut, D., Graham, F.L., Lillicrap, D. :
Helper-dependent adenoviral vectors mediate therapeutic factor VIII expression for several months with minimal accompanying toxicity in a canine model of severe hemophilia A. Blood 103:804-10, 2004. Pubmed reference: 14512318. DOI: 10.1182/blood-2003-05-1426.
2003 Scallan, C.D., Lillicrap, D., Jiang, H., Qian, X., Patarroyo-White, S.L., Parker, A.E., Liu, T., Vargas, J., Nagy, D., Powell, S.K., Wright, J.F., Turner, P.V., Tinlin, S.J., Webster, S.E., McClelland, A., Couto, L.B. :
Sustained phenotypic correction of canine hemophilia A using an adeno-associated viral vector Blood 102:2031-7, 2003. Pubmed reference: 12738670. DOI: 10.1182/blood-2003-01-0292.
2002 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 87:659-65, 2002. Pubmed reference: 12008949.
Lozier, J.N., Dutra, A., Pak, E., Zhou, N., Zheng, Z.L., Nichols, T.C., Bellinger, D.A., Read, M., Morgan, R.A. :
The Chapel Hill hemophilia A dog colony exhibits a factor VIII gene inversion Proceedings of the National Academy of Sciences of the United States of America 99:12991-12996, 2002. Pubmed reference: 12242334. DOI: 10.1073/pnas.192219599.
Notley, C., Killoran, A., Cameron, C., Wynd, K., Hough, C., Lillicrap, D. :
The canine factor VIII 3 '-untranslated region and a concatemeric hepatocyte nuclear factor 1 regulatory element enhance factor VIII transgene expression in vivo Human Gene Therapy 13:1583-1593, 2002. Pubmed reference: 12228013. DOI: 10.1089/10430340260201671.
2001 Gallo-Penn, A.M., Shirley, P.S., Andrews, J.L., Tinlin, S., Webster, S., Cameron, C., Hough, C., Notley, C., Lillicrap, D., Kaleko, M., Connelly, S. :
Systemic delivery of an adenoviral vector encoding canine factor VIII results in short-term phenotypic correction, inhibitor development, and biphasic liver toxicity in hemophilia A dogs Blood 97:107-113, 2001. Pubmed reference: 11133749.
2000 Clark, P., Hooper, C., MacDonald, M. :
Haemophilia A in a litter of Siberian huskies New Zealand Veterinary Journal 48:60-62, 2000.
Mischke, R. :
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 6:135-139, 2000. Pubmed reference: 10792470.
Mischke, R. :
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 6:575-580, 2000. Pubmed reference: 11012705.
1999 Brooks, M. :
Hereditary bleeding disorders in dogs and cats Veterinary Medicine 94:555-564, 1999.
Brooks, M. :
A review of canine inherited bleeding disorders: Biochemical and molecular strategies for disease characterization and carrier detection J Hered 90:112-8, 1999. Pubmed reference: 9987916. DOI: 10.1093/jhered/90.1.112.
Gallo-Penn, A.M., Shirley, P.S., Andrews, J.L., Kayda, D.B., Pinkstaff, A.M., Kaloss, M., Tinlin, S., Cameron, C., Notley, C., Hough, C., Lillicrap, D., Kaleko, M., Connelly, S. :
In vivo evaluation of an adenoviral vector encoding canine factor VIII: High-level, sustained expression in hemophiliac mice Human Gene Therapy 10:1791-1802, 1999. Pubmed reference: 10446919. DOI: 10.1089/10430349950017473.
Gerber, B., Taboada, J., Lothrop, C.D., Busato, A., Hosgood, G., Goodman, S.A., Gaschen, F.P. :
Determination of normal values using an automated coagulation timer for activated coagulation time and its application in dogs with hemophilia Journal of Veterinary Internal Medicine 13:433-436, 1999. Pubmed reference: 10499726.
Lutze, G., Kutschmann, K., Thomae, K., Franke, D. :
Successful treatment of canine haemophilia A with porcine factor VIII [German] Praktische Tierarzt 80:664-+, 1999.
Thompson, M.S., Kreeger, J.M. :
Acute paraplegia in a puppy with hemophilia A Journal of the American Animal Hospital Association 35:36-37, 1999. Pubmed reference: 9934926.
1998 Cameron, C., Notley, C., Hoyle, S., Mcglynn, L., Hough, C., Kamisue, S., Giles, A., Lillicrap, D. :
The canine factor VIII cDNA and 5' flanking sequence Thromb Haemost 79:317-22, 1998. Pubmed reference: 9493583.
Stokol, T., Parry, B.W. :
Efficacy of fresh-frozen plasma and cryoprecipitate in dogs with Von-Willebrands-disease or hemophilia a Journal of Veterinary Internal Medicine 12:84-92, 1998. Pubmed reference: 9560764.
1997 Clark, P., Parry, B.W. :
Cytogenetic analysis of german shepherd dogs with haemophilia a Australian Veterinary Journal 75:521-522, 1997. Pubmed reference: 9258429.
Clark, P., Bowden, D.K., Parry, B.W. :
Studies to detect carriers of haemophilia A in German Shepherd dogs using diagnostic DNA polymorphisms in the human factor VIII gene Veterinary Journal 153:71-74, 1997. Pubmed reference: 9125358.
Stokol, T., Trepanier, L., Parry, B.W., Finnin, B.C. :
Pharmacokinetics of von Willebrand factor and factor VIII in canine von-Willebrand-disease and haemophilia A Research in Veterinary Science 63:23-27, 1997. Pubmed reference: 9368952.
Wardrop, K.J., Lewis, D., Marks, S., Buss, M. :
Posttransfusion purpura in a dog with hemophilia a Journal of Veterinary Internal Medicine 11:261-263, 1997. Pubmed reference: 9298482.
1996 Connelly, S., Mount, J., Mauser, A., Gardner, J.M., Kaleko, M., Mcclelland, A., Lothrop, C.D. :
Complete short-term correction of canine hemophilia A by in vivo gene therapy Blood 88:3846-3853, 1996. Pubmed reference: 8916949.
Graham, J.B. :
The haemophilic dogs of Chapel Hill, North Carolina Haemophilia 2:255-258, 1996.
Joseph, S.A., Brooks, M.B., Coccari, P.J., Riback, S.C. :
Hemophilia A in a German shorthaired pointer - clinical presentations and diagnosis Journal of the American Animal Hospital Association 32:25-28, 1996. Pubmed reference: 8963732.
Mischke, R., Ramirez, P.A.R., Deniz, A., Hanies, R., Otto, K. :
Haemophilia A in the dog - symptoms, blood coagulation analysis and therapy [German] Berl Munch Tierarztl Wochenschr 109:279-87, 1996. Pubmed reference: 9005837.
Tennant, B. :
The problem of inherited diseases .3. Haemophilia in the German Shepherd Journal of Small Animal Practice 37:405-406, 1996. Pubmed reference: 8872944.
1995 Stokol, T., Parry, B.W. :
Stability of von Willebrand factor and factor VIII in canine cryoprecipitate under various conditions of storage Research in Veterinary Science 59:152-155, 1995. Pubmed reference: 8525105.
Stokol, T., Parry, B.W. :
Stability of canine factor VIII and von Willebrand factor antigen concentration in the frozen state Research in Veterinary Science 59:156-159, 1995. Pubmed reference: 8525106.
1994 Stigler, J. :
The factor-VIII-complex and its role in inherited coagulation disorders in dogs. Praktische Tierarzt 75:87, 1994.
1993 Brooks, M., Catalfamo, J. :
Buccal mucosa bleeding time is prolonged in canine models of primary hemostatic disorders. Thromb Haemost 70:777-80, 1993. Pubmed reference: 8128434.
Mansell, P.D., Parry, B.W., Anderson, G.A. :
Detection of Canine Carriers of Haemophilia A Using Factor- VIII Activity and Vonwillebrand Factor Antigen Concentration Preventive Veterinary Medicine 16:133-139, 1993.
Mischke, R. :
Influence of the Factor-VIII - C-Activity on the Activated Partial Thromboplastin Time (aPTT) in Dogs - Usefulness of the aPTT as a Screening Test for Canine Haemophilia-A Deutsche Tierarztliche Wochenschrift 100:219-222, 1993. Pubmed reference: 8339706.
Nichols, T.C., Bellinger, D.A., Reddick, R.L., Smith, S.V., Koch, G.G., Davis, K., Sigman, J., Brinkhous, K.M., Griggs, T.R., Read, M.S. :
The Roles of von Willebrand Factor and Factor-VIII in Arterial Thrombosis - Studies in Canine von Willebrand Disease and Hemophilia-A Blood 81:2644-2651, 1993. Pubmed reference: 8490173.
Stefanon, G., Stefanon, B., Dodds, W.J. :
Inherited and Acquired Canine Bleeding Disorders in Northeastern Italy Canine Practice 18:15-23, 1993.
Tinlin, S., Webster, S., Giles, A.R. :
The Development of Homologous (Canine/Anticanine) Antibodies in Dogs with Haemophilia-A (Factor-VIII Deficiency) - A 10- Year Longitudinal Study Thrombosis and Haemostasis 69:21-24, 1993. Pubmed reference: 8446933.
1992 Fitch, R., Wardrop, J. :
Hemophilia A in a German Shepherd Dog Canine Practice 17:19-23, 1992.
Mansell, P.D., Parry, B.W. :
Changes in Factor 8 Activity and Vonwillebrand-Factor Antigen Concentration with Age in Dogs British Veterinary Journal 148:329-337, 1992. Pubmed reference: 1498645. DOI: 10.1016/0007-1935(92)90085-F.
Mansell, P.D., Parry, B.W. :
Effect of Acepromazine, Xylazine and Thiopentone on Factor VIII Activity and Vonwillebrand Factor Antigen Concentration in Dogs Australian Veterinary Journal 69:187-190, 1992. Pubmed reference: 1530553.
Ni, H.Y., Giles, A.R. :
Normalization of the Haemostatic Plugs of Dogs with Haemophilia-A (Factor-VIII Deficiency) Following the Infusion of a Combination of Factor-Xa and Phosphatidylcholine/Phosphatidylserine Vesicles Thrombosis and Haemostasis 67:264-271, 1992. Pubmed reference: 1621248.
1991 Grondalen, J., Sjaastad, O., Teige, J. :
Enostosis (Panosteitis) in 3 Dogs Suffering from Hemophilia-A Canine Practice 16:10-14, 1991.
Horvath, L., Elodi, Z. :
Hereditary Haemophilia (Haemophilia-A) in a German Shepherd Dog Magyar Allatorvosok Lapja 46:29-32, 1991.
Johnstone, I.B., Keen, J., Halbert, A., Crane, S. :
Stability of Factor-VIII and Vonwillebrand Factor in Canine Blood Samples During Storage Canadian Veterinary Journal-Revue Veterinaire Canadienne 32:173-175, 1991.
Mansell, P.D., Parry, B.W. :
Stability of Canine Factor-VIII Activity and Vonwillebrand Factor Antigen Concentration Invitro Research in Veterinary Science 51:313-316, 1991. Pubmed reference: 1780587.
Mansell, P.D., Parry, B.W. :
Changes in Factor-8- Coagulant Activity and Vonwillebrand Factor Antigen Concentration After Subcutaneous Injection of Desmopressin in Dogs with Mild Hemophilia-A Journal of Veterinary Internal Medicine 5:191-194, 1991. Pubmed reference: 1920255.
1990 Mansell, P.D., Parry, B.W., Vanorsouw, P.J. :
Haemophilia-A in a Family of Miniature Poodles Australian Veterinary Journal 67:420-421, 1990. Pubmed reference: 2085303.
Mertens, K., Briët, E., Giles, A.R. :
The role of factor VII in haemostasis: infusion studies of factor VIIa in a canine model of factor VIII deficiency. Thromb Haemost 64:138-44, 1990. Pubmed reference: 2274919.
1989 Brinkhous, K.M., Hedner, U., Garris, J.B., Diness, V., Read, M.S. :
Effect of recombinant factor VIIa on the hemostatic defect in dogs with hemophilia A, hemophilia B, and von Willebrand disease. Proc Natl Acad Sci U S A 86:1382-6, 1989. Pubmed reference: 2784006. DOI: 10.1073/pnas.86.4.1382.
Chabbat, J., Hampikian-Lenin, S., Toully, V., Gaillandre, A., Péjaudier, L., Steinbuch, M. :
A human factor VIIa concentrate and its effects in the hemophilic A dog. Thromb Res 54:603-12, 1989. Pubmed reference: 2789440.
Mansell, P.D., Parry, B.W. :
Stability of canine factor VIII: coagulant in vitro Canadian Journal of Veterinary Research 53:264-267, 1989. Pubmed reference: 2504474.
1988 Fogh, J.M., Fogh, I.T. :
Inherited coagulation disorders. Vet Clin North Am Small Anim Pract 18:231-43, 1988. Pubmed reference: 3282382. DOI: 10.1016/s0195-5616(88)50018-9.
Fogh, J.M. :
A study of hemophilia A in German Shepherd dogs in Denmark Veterinary Clinics of North America, Small Animal Practice 18:245-254, 1988.
Giles, A.R., Tinlin, S., Hoogendoorn, H., Fournel, M.A., Ng, P., Pancham, N. :
In vivo characterization of recombinant factor VIII in a canine model of hemophilia A (factor VIII deficiency). Blood 72:335-9, 1988. Pubmed reference: 3134068.
Littlewood, J.D. :
Haemophilia A (factor VIII deficiency) in German Shepherd dogs Journal of Small Animal Practice 29:117-128, 1988.
Parry, B.W., Howard, M.A., Mansell, P.D., Hollaway, S.A. :
Haemophilia A in German shepherd dogs Australian Veterinary Journal 65:276-279, 1988. Pubmed reference: 3142453.
Parry, B.W., Holloway, S.A., Birch, D.J., Mackin, A.J. :
Haemophilia A in a cocker spaniel dog. Aust Vet J 65:326-7, 1988. Pubmed reference: 3196251.
Vander Velden, P., Giles, A.R. :
A detailed morphological evaluation of the evolution of the haemostatic plug in normal, factor VII and factor VIII deficient dogs. Br J Haematol 70:345-55, 1988. Pubmed reference: 3207628.
1986 Fogh, J.M. :
[Haemophilia A in German Shepherd dogs in Denmark] Dansk Veterinaertidsskrift 69:938-940, 1986.
Hein, H. :
Haemophilia A in German shepherd dogs. Vet Rec 118:619, 1986. Pubmed reference: 3727330.
Pijnappels, M.I., Briët, E., van der Zwet, G.T., Huisden, R., van Tilburg, N.H., Eulderink, F. :
Evaluation of the cuticle bleeding time in canine haemophilia A. Thromb Haemost 55:70-3, 1986. Pubmed reference: 3085267.
1985 Brinkhous, K.M., Sandberg, H., Garris, J.B., Mattsson, C., Palm, M., Griggs, T., Read, M.S. :
Purified human factor VIII procoagulant protein: comparative hemostatic response after infusions into hemophilic and von Willebrand disease dogs. Proc Natl Acad Sci U S A 82:8752-6, 1985. Pubmed reference: 3936044. DOI: 10.1073/pnas.82.24.8752.
1982 Dodds, W.J. :
An effective mass-screening program for animal models of the inherited bleeding disorders. Prog Clin Biol Res 94:117-32, 1982. Pubmed reference: 6981819.
Giles, A.R., Tinlin, S., Greenwood, R. :
A canine model of hemophilic (factor VIII:C deficiency) bleeding. Blood 60:727-30, 1982. Pubmed reference: 6809076.
1980 Spurling, N.W. :
Hereditary disorders of haemostasis in dogs: a critical review of the literature Veterinary Bulletin 50:151-173, 1980.
1977 Gentry, P.A., Johnstone, I.B., Sanford, S.E. :
Diagnosis of classic hemophilia (Hemophilia A) in a standard Poodle Canadian Veterinary Journal 18:79-81, 1977.
1975 Aufderheide, W.M., Skinner, S.F., Kaneko, J.J. :
Clearance of cryoprecipitated factor VIII in canine hemophilia A American Journal of Veterinary Research 36:367-370, 1975. Pubmed reference: 1124873.
Slappendel, R.J. :
Hemophilia A and hemophilia B in a family of French bulldogs Tijdschr Diergeneeskd 100:1075-88, 1975. Pubmed reference: 1209580.
1974 Dodds, W.J. :
Hereditary and acquired hemorrhagic disorders in animals. Prog Hemost Thromb 2:215-47, 1974. Pubmed reference: 4604529.
1973 Brinkhous, K.M., Davis, P.D., Graham, J.B., Dodds, W.J. :
Expression and linkage of genes for X-linked hemophilias A and B in the dog. Blood 41:577-85, 1973. Pubmed reference: 4688873.
Hampton, J.W., Buckner, R.G., Gunn, C.G., Miller, L.R., Mayes, J.S. :
Canine hemophilia in Beagles: genetics, site of factor VIII synthesis, and attempts at experimental therapy Haemophilia. Proceedings of the Seventh Congress of the World Federation of Haemophilia, May 17-20, 1971, Tehran, Iran :?, 1973.
1968 Davis, P.D. :
Canine double heterozygotes for hemophilia A and B. Federation Proceedings 27:627, 1968.
Norman, J.C., Covelli, V.H., Sise, H.S. :
Transplantation of the spleen (Editorial) Annals of Internal Medicine 78:700-704, 1968.
1967 Pick, J.R., Goyer, R.A., Graham, J.B. :
Subluxation on the carpus in dogs: a genetic defect on the X-chromosome closely linked to the locus for hemophilia A Federation Proceedings 26:358 only, 1967.
1965 White, J.M., Holm, G.C. :
Colony of Hemophilic Dogs. Science 150:1766, 1965. Pubmed reference: 17841958. DOI: 10.1126/science.150.3705.1766.
1963 Brock, W.E., Buckner, R.G., Hampton, J.W., Bird, R.M., Wultz, C.E. :
Canine hemophilia-establishment of a new colony Archives of Pathology 76:464-469, 1963. Pubmed reference: 14054168.
1957 Wagner, R.H. :
Antihemophilic factor (AHF): plasma levels after administration of AHF preparations to haemophilic dogs Proceedings of the Society for Experimental Biology and Medicine 96:152-155, 1957. Pubmed reference: 13485042.
1955 Swanton, M.C., Brinkhous, K.M. :
Hemophilic arthropathy in dogs American Journal of Pathology 31:596-597, 1955.
1950 Brinkhous, K.M., Graham, J.B. :
Hemophilia in the female dog. Science 111:723-4, 1950. Pubmed reference: 15431070.
1949 Graham, J.B., Buckwalter, J.A., Hartley, L.J., Brinkhous, K.M. :
Canine hemophilia; observations on the course, the clotting anomaly, and the effect of blood transfusions. J Exp Med 90:97-111, 1949. Pubmed reference: 18136192. DOI: 10.1084/jem.90.2.97.
1948 Hutt, F.B., Rickard, C.G., Field, R.A. :
Sex-linked hemophilia in dogs Journal of Heredity 39:2-9, 1948.
1946 Field, R.A., Rickard, C.G., Hutt, F.B. :
Hemophilia in a family of dogs. Cornell Veterinarian 36:285, 1946.
1938 Merkens, J. :
Haemophile bij Honden Journal Ned. Ind. Bladen v Diergeneesk en Dierant. 50:149-151, 1938.

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