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

IV. Disorders of Hemostasis
315
b. Vitamin K-Dependent Factor Deficiencies
(Prothrombin, FVII, FIX, FX, Protein C, Protein S)
The presence of vitamin K is essential to the function of
several procoagulant and anticoagulant proteins, including
prothrombin, FVII, FIX, FX, protein C, and protein S.
These vitamin K-dependent factors rely on posttranslational
carboxylation to allow binding of calcium and subsequent
binding to negatively charged phospholipid membranes
( Dowd et al ., 1995a ). Before participation in the carboxylation
of the vitamin K-dependent proteins, conversion of
vitamin K 1 to its biologically active form, vitamin K hydroquinone
(vitamin K 1 H 2 ), through an NADH-dependent
reductase is necessary ( Dowd et al ., 1995b ). The oxidation
of vitamin K 1 H 2 to vitamin K 1 2,3 epoxide occurs
simultaneously with, and provides energy for, carboxylation
of the glutamic acid residue through γ -glutamyl
carboxylase ( Dowd et al ., 1995b ). The resultant vitamin
K 1 2,3 epoxide is then reduced to vitamin K 1 through
vitamin K epoxide reductase, completing the cycle.
Inherited defects in the vitamin K cycle have been
identified in Devon Rex cats and Rambouillet sheep. Initial
reports in related Devon Rex cats observed multiple factor
deficiencies that resembled anticoagulant toxicity and were
responsive to vitamin K therapy ( Maddison et al ., 1990 ).
These cats presented with hematomas, intrathoracic hemorrhage,
and hemorrhage in the bladder, sublumbar area,
and perineum ( Maddison et al ., 1990 ). The specific mechanism
for the disorder was not identified in that report. A
later case report on two littermates was able to identify a
decreased affinity of the γ -glutamyl carboxylase for vitamin
K ( Soute et al ., 1992 ). Investigation into a flock of
Rambouillet sheep experiencing increased lamb mortality
because of ineffective hematopoiesis also identified
a defect in γ -glutamyl carboxylase, specifically a single
nucleotide polymorphism resulting in truncation of the
enzyme ( Johnson et al ., 2006a, 2006b ). The affected lambs
continually bled from the umbilicus and experienced subcutaneous
and body cavity hemorrhage, resulting in death
( Johnson et al ., 2006b ). Breeding data from the flock indicated
an autosomal recessive trait ( Johnson et al ., 2006b ).
Unlike the defect in the Devon Rex cats, vitamin K therapy
was not effective in these lambs ( Johnson et al ., 2006b ).
To the authors ’ knowledge, there has been a single case
report of naturally occurring protein C deficiency in animals.
A 2-year-old Thoroughbred colt was diagnosed with
a functional deficiency in protein C resulting in recurrent
venous thrombosis ( Edens et al ., 1993 ). Although a specific
genetic defect was not identified, it was suggested that
this deficiency was a result of either a primary inherited
abnormality in protein C or an abnormal posttranslational
γ -carboxylation ( Edens et al ., 1993 ).
c. Factor VII Deficiency
FVII deficiency is well described in beagles but has also
been documented in Alaskan malamutes and a mixed-breed
dog ( Macpherson et al ., 1999 ; Mills et al ., 1997 ). Presenting
hemorrhagic signs in nonbeagle dogs have included mucosal
hemorrhage, subcutaneous bruising, and excessive surgical
hemorrhage. Although clinical manifestations are
occasionally reported in beagles, the coagulation deficiency
is often an incidental finding in beagle colonies when routine
coagulation screens are performed before experimental studies
( Spurling et al ., 1972, 1974 ). Routine OSPT is prolonged
and FVII coagulant activity decreased in affected dogs; however
these are not reliable methods to detect carrier status
(Callan et al ., 2006 ). In contrast, both homozygous and heterozygous
beagles appear to have impaired clotting profiles
in rotational thromboelastography when compared to normal
canine plasma ( Callan et al ., 2006 ). A missense mutation has
been identified in beagles and is consistent within the breed
(Callan et al ., 2006 ).
d. Factor VIII Deficiency (Hemophilia A)
Hemophilia A is one of the most common inherited coagulopathies
in dogs, having been identified in many breeds, and
it has also been reported in cats, cattle, horses, and an alpaca
(Cotter et al ., 1978 ; Healy et al ., 1984 ; Henninger, 1988 ;
Miesner and Anderson, 2006 ). Reported hemorrhagic signs
have included umbilical hemorrhage, gingival bleeding at
teething, hematomas, hemarthrosis, intraspinal hemorrhage,
excessive surgical bleeding, and delayed rebleeding postsurgery
( Fogh, 1988 ; Miesner and Anderson, 2006 ; Thompson
and Kreeger, 1999 ). Mildly affected animals (FVIII activity
of 5% or higher) do not tend to bleed spontaneously and
are generally able to maintain adequate hemostasis, whereas
moderately affected animals (FVIII activity of 2% to 5%) are
more likely to experience severe sequelae to minor trauma,
and severely affected animals (FVIII activity less than 2%)
may bleed spontaneously ( Mansell, 2000 ). The buccal mucosal
bleeding time (see Sections III.B.1.a and b) is within reference
intervals for FVIII-deficient dogs; however, cuticle
bleeding time is prolonged ( Brooks and Catalfamo, 1993 ;
VanderVelden and Giles, 1988 ). Evaluation of biopsies from
experimentally injured cuticles, using light and electron
microscopy, have shown significant differences in the platelet
component of the platelet plug as well as gross abnormalities
in fibrinous transformation in FVIII-deficient dogs compared
to normal dogs ( Fogh and Fogh, 1988 ; VanderVelden
and Giles, 1988 ). The platelet plugs were larger, often fragmented,
and frequently did not appear to be associated with
the vessel. Platelets within the plug appeared quiescent
(remained granular and lack of OCS dilatation), and minimal
fibrinous transformation of the plug occurred ( VanderVelden
and Giles, 1988 ). The changes noted in FVIII-deficient animals
cannot be extrapolated to other secondary hemostatic
deficiencies. Under the same conditions, the sequential events
that occurred during clot formation in normal dogs were also
observed in FVIII-deficient dogs; however, a time delay was
apparent ( VanderVelden and Giles, 1988 ). The rebleeding
phenomenon described in hemophiliacs can be explained by