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

IV. Disorders of Hemostasis
319
thrombin during endotoxemia appears to occur from activation
of the TF pathway via FVIIa. Inhibition of this pathway
resulted in complete absence of thrombin generation in
experimental primate studies ( Biemond et al ., 1995 ; Pixley
et al ., 1993 ), and administration of TFPI completely abrogates
this response (DeJonge et al ., 2000). The source of
TF may be from activated monocytes, other leukocytes, or
altered endothelium ( Levi, 2004 ). The role of neutrophils in
the pathogenesis of DIC has been examined, and it appears
they may interact with platelets and stimulate TF production
and fibrin formation ( Goel and Diamond, 2001 ). Neutrophil
elastase also has the potential to degrade fibrinolytic proteases
( Moir et al ., 2002 ), thereby minimizing clot dissolution.
Additionally, the natural anticoagulant pathways may
become inhibited, which would further amplify thrombin
generation. AT activity can be markedly reduced because
of consumption from enhanced thrombin generation, degradation
by elastase released by neutrophils, and possibly
decreased synthesis if liver synthetic function is impaired
( Levi, 2005 ). The protein C system can similarly become
exhausted by enhanced consumption, impaired hepatic synthesis,
and down-regulation of TM expression on endothelial
cells as part of the change from an antithrombotic to a prothrombotic
milieu ( Faust et al ., 2001 ) (see Section II.A).
Fibrinolysis is impaired due to rapidly increased levels
of PAI-1, which suppresses plasminogen activation, and
therefore subsequently any clots that develop are not as
efficiently degraded. Many of the hemostatic abnormalities
that occur during DIC can be attributed to up-regulation
of proinflammatory cytokines such as tumor necrosis
factor alpha (TNF-alpha) and interleukin-1 (IL-1), which
then promote a procoagulatory endothelial phenotype. It is
also known that parts of the coagulation cascade, once activated,
can also stimulate further activation of inflammation
as well. For example, thrombin, via PARs on cell membranes,
activates additional inflammatory mediators. So it
is indeed a bidirectional process once either inflammation
or coagulation is stimulated. Additionally, suppression of
the protein C pathway may result in a proinflammatory
state because it has anti-inflammatory properties ( Yuksel
et al ., 2002 ). It must be emphasized that different disease
states can result in DIC by a different mechanism. For
example, some neoplastic cells may directly express TF or
other procoagulant molecules ( Rickles and Falanga, 2001 ),
whereas DIC secondary to trauma or burns is related to
systemic release of fat and phospholipids ( Gando, 2001 ).
The diagnosis of DIC is based on clinical signs of the
primary disease, as well as those associated with both hemorrhage
and thrombosis, in conjunction with abnormal laboratory
tests. Overt hemorrhage is often more prominent in
animals with DIC, which may reflect the stage the syndrome
is detected, or it may be that thrombosis is not detected readily
antemortem. Because there is no single test that confirms
the present of DIC, most often the diagnosis is made on
a series of tests in an animal with an appropriate clinical
context in which DIC can develop. Molecular markers of
activation of coagulation or fibrin formation such as prothrombin
fragment F1 2 and soluble fibrin concentration
may be the most sensitive indicators of the presence of DIC,
but they are poorly specific and not widely available ( Levi,
2004 ).
The common laboratory test abnormalities include
thrombocytopenia; presence of schistocytes on a blood
smear; prolonged OSPT and aPTT; increased levels of
indicators of fibrinolysis (FDPs, d-dimers); and decreased
fibrinogen, AT, protein C, and coagulation factors. Some of
these tests are more commonly altered than others, and serial
measurements may sometimes be more helpful than a single
sample. Fibrinogen concentration can sometimes actually be
within the reference interval or even elevated as it is also an
acute phase reactant in some species. Furthermore, although
elevated products of fibrinolysis do occur during DIC, they
can be increased in other disease states as well, which limits
their specificity. The International Society on Thrombosis
and Haemostasis (ISTH) has developed a scoring system to
facilitate establishing the presence of DIC in human patients
using a combination of results of different tests in a patient
with a disease that can predispose to the condition and has
a reported sensitivity and specificity of 90% (Bakhtiari
et al ., 2004 ).
DIC has been documented in many species of domestic
animals ( Bateman et al ., 1999b ; Dolente et al ., 2002 ;
Irmak and Turgut, 2005 ) but is most commonly reported in
dogs. The most common precipitating diseases are listed in
Table 10-8 .
5. Vitamin K Antagonism or Defi ciency
Anticoagulant rodenticides are the most common cause of
acquired vitamin K-dependent factor deficiencies. Their
action is through inhibition of the vitamin K epoxide reductase
enzyme, preventing recycling of vitamin K and resulting
in depletion of vitamin K 1 H 2 (Murphy, 2002 ). The
development of resistance, by rodents, to the first generation
anticoagulant rodenticides (e.g., warfarin) necessitated
the development of second-generation compounds (e.g.,
brodifacoum, bromadiolone) with more potent and persistent
action ( Boermans et al ., 1991 ; Park and Leck, 1982 ). In
experimental exposure to anticoagulant rodenticides, initial
clinical signs generally include anorexia and somnolence,
whereas clinical reports generally identify dyspnea, lethargy,
and coughing/hemoptysis as the most frequent initial
presenting complaints ( Boermans et al ., 1991 ; Forbes et al .,
1973 ; Sheafor and Couto, 1999 ). Additional clinical signs
can often include epistaxis, melena, lameness, spontaneous
subcutaneous hematoma formation, hematuria, collapse,
abdominal distension, and sudden death ( DuVall et al .,
1989 ; Sheafor and Couto, 1999 ). Case reports of rodenticide
toxicity in neonates provide circumstantial evidence that
rodenticides can cross the placenta and therefore should be