Clinical Biochemistry of Domestic Animals (Sixth Edition) - UMK ...

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Chapter | 10 Hemostasis
the role of TAFI (see Section II.C.4.c) in fibrinolysis inhibition.
Although a small amount of thrombin formation is sufficient
to stabilize the initial platelet plug, the secondary burst
of thrombin that occurs in the propagation phase of coagulation
is required for the activation of TAFI ( Mosnier et al .,
2001 ). In hemophilia A, this secondary burst of thrombin formation
is inadequate, resulting in deficient TAFI and fibrinolysis
of the initial clot ( Monroe and Hoffman, 2006 ; Mosnier
et al ., 2001 ). Hemophilia A is an X-linked recessive trait,
and therefore males are most commonly affected. Laboratory
findings in homozygotes generally include prolonged aPTT,
OSPT within reference intervals, and decreased FVIII activity.
There is a poor correlation between the degree of prolongation
of the aPTT and the activity of FVIII in plasma
( Mansell, 2000 ). Heterozygotes are asymptomatic, and typical
laboratory testing does not reliably discriminate between
normal and carrier animals. Recently, a marker allele associated
with the hemophilia A phenotype has been identified in
a golden retriever family and was able to define carrier status
(Brooks et al ., 2005 ).
e. Factor IX Deficiency (Hemophilia B)
Based on clinical signs, hemophilia B is indistinguishable
from hemophilia A. Generally, it is considered that clinical
signs are more severe in young and large-breed dogs
( Nakata et al ., 2006 ). As with FVIII deficiency, this disorder
is an X-linked recessive trait and has been reported in
both dogs and cats. Laboratory testing reveals a prolonged
aPTT, a normal OSPT, and a decrease in plasma FIX activity.
In contrast to the variability seen in hemophilia A, FIX
activity is generally low ( 5%) in homozygotes ( Mansell,
2000 ). In addition, mild decreases in FIX activity appear
more consistent in heterozygotes of hemophilia B, and
therefore factor activity screening is more reliable in their
identification ( Mansell, 2000 ). A variety of genetic mutations
have been identified in dogs, and recently two distinct
nucleotide changes were identified in two cats ( Evans
et al ., 1989 ; Goree et al ., 2005 ; Gu et al ., 1999 ).
f. Factor X Deficiency
Canine FX deficiency was first reported in a breeding colony
of cocker spaniels in 1973 ( Dodds, 1973 ). This colony
was experiencing increased morbidity and mortality in
newborn puppies, within 7 to 10 days of birth, from obvious
hemorrhagic complications ( Dodds, 1973 ). Dogs with
factor activities between 18% and 68% experienced moderate
to severe hemorrhagic signs, and the trait appeared to
be lethal in many of these dogs ( Dodds, 1973 ). FX deficiency
has also been identified in a Jack Russell terrier and
domestic shorthair cat ( Cook et al ., 1993 ; Gookin et al .,
1997 ). In humans, this deficiency is inherited as an autosomal
recessive trait; however, in the initial canine report
an autosomal dominant inheritance, with incomplete penetrance,
was suspected ( Dodds, 1973 ). aPTT, OSPT, and
Russell viper venom time (RVVT) are all prolonged in
affected animals, factor X activity is decreased, and thrombin
time is within reference intervals.
Acquired FX deficiency resulting from Hymenoxys odorata
(bitterweed) has been demonstrated experimentally in
sheep ( Steel et al ., 1976 ). This annual weed produces illness
and death, as early as 24 h postingestion, in sheep and
occasionally cattle. Experimentally exposed sheep had prolongation
of both the OSPT and aPTT within 3 days ( Steel
et al ., 1976 ). Plasma FX activity was decreased; however,
all other specific factors remained within reference intervals
( Steel et al ., 1976 ).
g. Factor XI Deficiency
Congenital FXI deficiency is uncommon in animals;
however, it has been identified in dogs, cattle, and more
recently in a cat ( Dodds and Kull, 1971 ; Gentry et al .,
1975 ; Troxel et al ., 2002 ). Hemorrhagic signs associated
with this deficiency tend to be mild; however, they can be
substantial after challenge with surgery or severe trauma
( Gentry, 2000a ). FXI deficiency is transmitted as an autosomal
recessive trait, and although the degree of reduced
factor activity varies between species, in general homozygotes
have less than 11% FXI activity and heterozygotes
vary from 23% to 48% ( Gentry, 2000a ; Gentry and Ross,
1994 ; Knowler et al ., 1994 ). Prolongation of the aPTT, an
OSPT within reference intervals, and a decreased plasma
FXI activity are typical of homozygous animals. The
aPTT has been proven inadequate to identify heterozygotes,
and identification based on FXI activity has proven
difficult because of an overlap in the range of activities
between carrier and normal animals ( Gentry and Ross,
1986 ; Kunieda et al ., 2005 ). Two distinct genetic mutations,
both insertions, have been identified in the Holstein
and Japanese black cattle, thus providing a more accurate
diagnostic approach to the heterozygote in this species
( Kunieda et al ., 2005 ; Marron et al ., 2004 ).
To the authors ’ knowledge, there has been a single
report of acquired FXI deficiency. A 5-year-old neutered
male cat without a previous history of hemorrhage was presented
with epistaxis. FXI activity was markedly decreased
( 5%), and mixing studies indicated the presence of an
inhibitor ( Feldman et al ., 1983 ). A systemic lupus erythematosus
(SLE) inhibitor was suspected on subsequent
detection of erythrocyte autoagglutination ( Feldman et al .,
1983 ). Marked intraperitoneal hemorrhage resulted in the
death of this patient.
h. Contact Factor Deficiencies
Of the contact factors, FXII (Hageman factor) deficiency is
the most common. This deficiency is generally associated
with cats, and an autosomal recessive mode of transmission
has been identified in this species ( Kier et al ., 1980 ).
Homozygotes for FXII deficiency have a factor activity of