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

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Chapter | 10 Hemostasis
a consideration in neonatal hemorrhagic disorders ( Munday
and Thompson, 2003 ).
Although anticoagulant toxicity is most common in
canine patients, accidental exposure can also occur in cats,
horses, and ruminants. Ruminants have historically been
thought more resistant to these rodenticides because of
rumenal degradation of the compounds ( Berny et al ., 2006 ).
It has recently been shown that there is no significant breakdown
of the rodenticides in the rumen, and oral bioavailability
of these compounds is excellent (79% for warfarin,
88% for bromadiolone) ( Berny et al ., 2006 ). Further, prolongation
of the OSPT was observed for both compounds;
however, no clinical signs of toxicosis were evident ( Berny
et al ., 2006 ). A prolonged OSPT is generally the initial
laboratory change in rodenticide toxicity because of the
relatively short half-life of FVII (4 to 6 h). With subsequent
decreases in FIX, FX, and prothrombin, a prolonged aPTT
develops. Interestingly, experimental brodifacoum toxicity
in the horse resulted in prolongation of the aPTT before
the OSPT was affected ( Boermans et al ., 1991 ). As a result
of this observation, it was proposed that clearance of vitamin
K-dependent factors in the horse may differ from that
in the dog and human ( Boermans et al ., 1991 ). The onset of
laboratory changes and clinical signs varies with the amount
and type of anticoagulant rodenticide consumed. In addition
to changes in routine coagulation tests (OSPT and aPTT),
the accumulation of the nonfunctional forms of the vitamin
K-dependent coagulation proteins (PIVKA) can be detected
by a commercial Thrombotest assay (see Section III.C).
In addition to anticoagulant rodenticides, ingestion
of moldy sweet clover (dicumarol) can result in vitamin
K-dependent coagulation factor deficiencies, acting through
the same mechanism. However, clinical signs generally
only develop after weeks of exposure ( Berny et al ., 2006 ).
Ingestion of sulfaquinoxaline, a poultry coccidiostat, has
also been reported to result in vitamin K-dependent factor
deficiencies in dogs through inhibition of vitamin K epoxide
reductase ( Neer and Savant, 1992 ; Preusch et al ., 1989 ).
6. Thrombosis
Pathological thrombus formation can occur in any vascular
structure and, depending on the extent of obstruction and
the tissue affected, can elicit a wide range and severity of
clinical signs. Acute dyspnea and hemoptysis is observed
with pulmonary thromboemboli, hematuria, and abdominal
pain with renal thrombosis and pain and paresis or paralysis
in with distal aortic thromboembolism in cats with cardiac
disease.
Although not frequently easily detected clinically, predisposition
to thrombosis can occur with many diseases
in various domestic species. Most often, thrombosis is
associated with an underlying disease process that causes
a disturbance of hemostatic processes, particularly those
that promote a hypercoagulable state. However, additional
abnormalities including inappropriate platelet and endothelium
activation may exist concurrently to exacerbate the
situation ( Darien, 2000a ) .
An example of a disease associated with a high risk for
thromboembolic complications in dogs is immune-mediated
hemolytic anemia (IMHA). Up to 50% of patients
with this disease develop thrombi, often in the pulmonary
system ( Balch and Mackin, 2007 ). These dogs are frequently
in a hypercoagulable state as a result of inflammatory
cytokine activation of endothelial cells from red blood
cell necrosis and hypoxia, vascular stasis from catheterization
and immobility, and enhanced platelet activation
( Weiss and Brazzell, 2006 ).
Other diseases associated with pathological thrombus
development include endotoxemia, heartworm disease,
hemangiosarcoma, hyperadrenocorticism, and various cardiac
diseases ( Darien, 2000a ) .
V. BEYOND HEMOSTASIS: INTERACTIONS
WITH INFLAMMATION
It has become quite well documented that there is a continuum
between the inflammatory response and the hemostatic
system and that activation of one system up-regulates
the other. Numerous recent reviews summarize this active
research area ( Esmon, 2005 ; Franchini et al ., 2007 ; Gear
and Camerini, 2003 ; Levi and van der Poll, 2005 ; Vincent,
2003 ; Zarbock et al ., 2007 ).
Inflammatory mediators can increase platelet production,
activate platelets, diminish endogenous anticoagulant
activity, initiate and contribute to propagation of the
coagulation cascade, increase fibrinogen concentration,
and inhibit fibrinolysis ( Esmon, 2005 ). Inversely, activation
of the hemostatic mechanism can cause the release of
inflammatory mediators from activated platelets and endothelial
cells ( Table 10-9 ). Traditional figurative depictions
of either system rarely include elements of the other. More
recently, however, appreciation for interactions between
the two systems has become apparent. There are even some
structural similarities between proteins in the two systems,
which supports the theory of a parallel evolution ( Esmon,
2005 ). Examples include protein S with C4 binding protein,
endothelial cell protein C receptor with MHC class 1,
and TM’s similarity with lectins.
The release or enhanced expression of TF during
inflammation is central to the widespread activation of
coagulation observed during a systemic inflammatory
response. It has been proposed that phospholipid-rich microparticles
derived from leukocytes (especially monocytes)
or endothelial cells express TF, and this facilitates further
development of the thrombus via P-selectin-glycoprotein
ligand-1 and P-selectin binding, which brings platelets and
leukocytes into close approximation ( Day et al ., 2005 ).
The role of TF in inflammation is further corroborated by