SUMMARY OF CONTRIBUTION OF HEMOPHILIC DOGS 
TO KNOWLEDGE AND HUMAN WELFARE 
Kenneth M. Brinkhous* 
A canine animal model identical with an in- 
herited sex-linked human disease, hemophilia, 
has been of greatest value in elucidating the ba- 
sis of the disease and in developing a rational 
therapeutic regimen.^ This model has contrib- 
uted in two major ways : (a) by a study of the 
disease in the animals themselves, and (b) by 
supplying a ready source of blood plasma for 
biochemical and physiological studies of a 
plasma procoagulant, the antihemophilic factor 
(AHF, Factor VIII), In the first category, ex- 
periments, with the deficient animals included 
studies on inheritance, methodology for diag- 
nosis, pathophysiology, and therapy. In regard 
to inheritance, it was demonstrated that classic 
hemophilia could be produced in females ^ and 
that with these females all major genetic crosses 
of recessive sex-linked Mendelian inheritance 
were for the first time completed.^ The low level 
of AHF in female carriers was verified and the 
diagnostic value of this test in identifying this 
class of females, even at birth, was demon- 
strated.* Genetic linkage studies with subluxa- 
tion of the carpus ^ and pseudohermaphrodit- 
ism ^ and chromosomal DNA replication were 
undertaken. By interbreeding with a strain of 
hemophilia B dogs, the loci of the two hemo- 
philia genes were shown to be widely separated, 
and a new strain of animals with double hemo- 
philia or hemophilia AB was established.^'^ In 
methodologic and pathophysiologic studies two 
bioassay methods were developed,!^-" and on 
one of these, the partial thromboplastin time, 
the diagnostic schema almost universally 
adopted in clinical laboratories is based." i2 The 
anticephalin hypothesis was tested. The short 
half-life and biphasic disappearance curves of 
transfused AHF 12.14,15 became the basis of 
scheduled plasma or concentrate therapy to 
• Department of Pathology, University of North Carolina, School 
of Medicine, Chapel Hill, North Carolina. 
maintain hemostasis. The rapid loss of AHF 
during clotting was established ^'^^ and the rela- 
tion of feedback mechanisms due to formation 
of thrombin ^'^•'^^ and plasmin (or fibrinolysin)^^ 
was shown, and the ineffectiveness of subcutan- 
eous and intramuscular routes for treatment 
was demonstrated. 
Through organ perfusion and organ trans- 
plantation studies, the role of the spleen as a 
site of storage of AHF 21-2* and the curative role 
of the transplanted normal liver were estab- 
lished. The role of the kidney was explored.^^ 
The resistance of AHF levels to total body ir- 
radiation was demonstrated.2'^ The finding that 
hemophilic dogs were resistant to diffuse intra- 
vascular coagulation (DIG) 28.29 -^^as the fore- 
runner of the paradox of treating DIG with 
anticoagulants, heparin and Dicumarol. 
By having a reliable AHF deficient plasma 
constantly available, the biochemical characteri- 
zation of AHF was started,^*'^"-^* and inter- 
mediate and high-potency concentrates (glycine- 
precipitated) for therapy of hemophilia were 
developed.35'36 AHF was shown to be a cryopro- 
tein, a forerunner of cryoprecipitate therapy.^^'^^ 
It was shown that an antibody to AHF char- 
acterized by a high degree of species specificity 
could be produced.^^ 
REFERENCES 
1. Graham, J. B., Buckwalter, J. A., Hartley, 
L. J., and Brinkhous, K. M. Canine hemophilia: 
Observations on the course, the clotting anomaly, 
and the effect of blood transfusions. J. Exp. Med. 
90:97, 1949. 
2. Brinkhous, K. M. and Graham, J. B. Hemophilia 
in the female dog. Science 111:723, 1950. 
3. Brinkhous, K. M. Hemophilia. Bull. N. Y. Acad. 
Sci. 3:325, 1954. 
4. Parks, B. J., Brinkhous, K. M., Harris, P. F., 
and Penick, G. D. Laboratory detection of female 
carriers of canine hemophilia. Thromb. Diath. 
Haemorrh. 12:368, 1964. 
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