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

IV. Disorders of Hemostasis
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less than 2%, whereas heterozygotes average approximately
50% ( Kier et al ., 1980 ). Laboratory evidence for this deficiency
includes a prolonged aPTT and decreased plasma
FXII activity. Cats are often identified incidentally during
routine coagulation screening and do not exhibit hemorrhagic
signs. An absence of FXII has been demonstrated as
a normal phenomenon in several species, including some
marine mammals, birds, and reptiles ( Robinson et al ., 1969 ).
This finding suggests that FXII is not integral to the coagulation
system, and similarly may explain the absence of
hemorrhage in deficient cats. FXII deficiency in combination
with other factor deficiencies has been reported in both
dogs and cats ( Dillon and Boudreaux, 1988 ; Littlewood and
Evans, 1990 ; Otto et al ., 1991 ; Randolph et al ., 1986 ).
Prekallikrein deficiency is rare; however, it has been
reported in the dog and in miniature and Belgian horses
( Chinn et al ., 1986 ; Geor et al ., 1990 ; Otto et al ., 1991 ;
Turrentine et al ., 1986 ). Excessive hemorrhage after castration
occurred in the proband Belgian horse, but in other
animals hemorrhagic signs were not present without concurrent
underlying disease or combination factor deficiencies.
Laboratory tests reveal a prolonged aPTT, and
decreased prekallikrein activity in this deficiency. In the
equine families examined, an autosomal recessive mode
of inheritance was suggested ( Geor et al ., 1990 ; Turrentine
et al ., 1986 ). In general, homozygotes exhibited markedly
decreased prekallikrein activities, and heterozygotes
exhibited mild to moderate decreases ( Geor et al ., 1990 ;
Turrentine et al ., 1986 ). Additional reports of contact factor
pathway deficiencies have included a horse and German
shorthaired pointer; however, definitive identification of
the specific factor deficiency was not possible ( Ainsworth
et al ., 1985 ; Lisciandro et al ., 2000 ). Bleeding diathesis
was not present in either case, despite challenge with ovariohysterectomy
in the German shorthaired pointer.
B. Acquired Disorders
1. Thrombocytopenia
Clinically relevant thrombocytopenias are generally
acquired; however, there are numerous etiologies, and
detailed discussion of each extends beyond the scope of
this chapter. Refer to Russell and Grindem (2000) , Scott
(2000) , Zimmerman (2000) and for more details. In general,
the pathogenesis of acquired thrombocytopenias can be
grouped into three categories: (1) decreased production, (2)
increased consumption or destruction, and (3) sequestration.
Decreased production can result from infectious agents (e.g.,
Ehrlichia spp., bovine viral diarrhea virus, feline leukemia
virus, equine infectious anemia virus), toxins, or drugs that
suppress bone marrow (such as chemotherapeutic agents,
estrogen, and NSAIDs); myelophthisis; or immune-mediated
mechanisms that target megakaryocytes. Increased destruction
of platelets is frequently associated with consumptive
coagulopathies (see Section IV.B.4) and immune-mediated
mechanisms. Immune-mediated thrombocytopenias can be
idiopathic (primary) or associated with systemic immune
disease, drug therapy, neoplasia, or infectious agents (secondary).
Finally, abnormal distribution or sequestration
(e.g., enlarged spleen) can result in decreased platelet numbers;
however, this tends not to be responsible for the more
dramatic cases of thrombocytopenia.
2. Platelet Dysfunction
As with acquired thrombocytopenias, acquired platelet
function disorders are numerous, and detailed discussion is
beyond the scope of this chapter (see Boudreaux [2000] ,
for more details). Briefly, uremia, increased FDPs (DIC or
liver failure), neoplasia, and hyperproteinemia or paraproteinemia
can impair adhesion of platelets. Several therapeutic
agents can also impede platelet function through
various mechanisms, including inhibition of the cyclooxygenase
enzyme (nonsteroidal anti-inflammatories),
inhibition of calcium influx across the platelet membrane
(calcium channel blockers), and inhibition of agonist
receptors ( β -lactam antibiotics) ( Boudreaux, 2000 ).
3. Liver Disease
The majority of coagulation proteins is synthesized in the
liver, and therefore, as seen with other products of the liver,
decreased synthesis occurs with severe decreases in functional
hepatic mass. Refer to recent reviews on hemostatic
abnormalities of liver disease in humans for a detailed discussion
( Lisman et al ., 2002 ; Senzolo et al ., 2006 ). Briefly,
the effect of liver disease is complex, as it is involved in
both procoagulant and anticoagulant systems. Therefore,
dysfunction can result in either hemorrhagic or thrombotic
complications ( Senzolo et al ., 2006 ). Dysfunction
can include decreased production of coagulation proteins
or production of abnormal proteins with altered function
( Lisman et al ., 2002 ). Studies comparing acute (toxicity
induced) liver failure and chronic cirrhosis have suggested
different mechanisms for coagulation factor deficiencies.
In acute failure, prothrombin, FV, FVII, and FX were significantly
reduced and proposed to result from a concurrent
increase in IL-6 and TNF- α that resulted in increased
TF expression ( Kerr et al ., 2003 ). Although TF activates
the thrombin-generating pathways (see Section II.C.3),
because of a simultaneous increase in thrombin-antithrombin
(TAT) complexes the activity of thrombin is suppressed,
effectively reducing the subsequent consumption
of FVIII, FIX, and FXI ( Kerr et al ., 2003 ). In fact, FVIII
levels were markedly elevated in acute liver failure, which
can assist in the differentiation of acute hepatic failure
from DIC, where FVIII levels would be decreased ( Kerr
et al ., 2003 ; Senzolo et al ., 2006 ). In contrast, prothrombin,
FV, FVII, FIX, and FX were found to decrease in similar