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Fe - Feline Medicine
CLOTTING AND COAGULATION DISORDERS IN CATS
Dr. Séverine Tasker
Department of Clinical Veterinary
Science
University of Bristol
Langford
Bristol BS40 5DU
United Kingdom
[email protected]
These affect the ability of the blood to coagulate.
Coagulation, the process of clot formation, is
achieved in vivo by a combination of primary and
secondary haemostasis (Stokol 2005). Although
clotting disorders usually refer to secondary
haemostatic disorders, primary haemostasis
will also be discussed briefly due to the close
integration and clinical need to differentiate
between the two.
OVERVIEW OF HAEMOSTASIS
Primary Haemostasis
This involves platelet adhesion, via Von
Willebrand factor (vWF), to the subendothelial
collagen, with ensuing activation and aggregation
of platelets, resulting in the formation of a
platelet plug. When platelets become activated,
phosphatidylserine (PS; previously platelet factor
3) becomes exposed on the platelet membrane and
acts as a scaffold for the assembly of coagulation
factors in secondary haemostasis. Thus primary
and secondary haemostasis are closely linked.
Primary haemostasis also involves an initial
reflex constriction of the blood vessel.
Secondary Haemostasis
This involves formation of fibrin by coagulation
factors to stabilise the primary haemostatic plug.
Classically secondary haemostasis has been
explained by the coagulation cascade which is
divided into intrinsic and extrinsic pathways
with a final common pathway (Figure 1). This
cascade is useful when interpreting diagnostic
haemostatic testing but does not reflect how
coagulation occurs in vivo. In vivo there is
extensive interaction between these pathways
with the extrinsic pathway (tissue factor) initiating
coagulation and the intrinsic pathway amplifying
it. Surface (or contact) activation is required for
in vitro clotting tests but is not required for in vivo
coagulation.
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Figure 1: Schematic Diagram of Secondary Haemostasis for Test Interpretation
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Most coagulation factors are protease enzymes
which circulate in an inactive form.
All
coagulation factors are synthesised in the liver.
The liver requires vitamin K for the synthesis of
Factors II, VII, IX and X.
Tertiary Haemostasis
Tertiary haemostasis consists of fibrinolysis to
break down the fibrin clot predominantly via the
action of plasmin cleaving fibrin.
Inhibitors
Limiting reactions ensure that clotting is localised
to the required area. Substances important
include antithrombin (AT) which, in association
with heparin, inactivates many of the coagulation
factors, and prostacyclin (PGI2), produced by
blood vessel endothelial cells, which inhibits
platelet aggregation and causes vasodilation.
APPROACH TO FELINE COAGULOPATHIES
History and Clinical Findings
Inherited disorders tend to present in younger
cats. It is important to find out the response of the
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cat to any previous trauma or surgery as severe
inherited disorders will usually have resulted in
bleeding complications. Information regarding
any bleeding problems in related animals should
be obtained. Recent exposure to toxins such as
rodenticides or drugs (e.g. aspirin, NSAIDs) that
can affect bleeding should be investigated.
Primary haemostatic disorders are characterised
by bleeding from mucosal surfaces (e.g.
haematuria, epistaxis), petechiae and prolonged
bleeding from cuts or venipuncture. Secondary
haemostatic disorders are characterised by more
severe bleeding into e.g. joints and body cavities,
haematomas, ecchymoses and delayed bleeding
from cuts.
Laboratory Investigation
Blood samples taken for the investigation of
bleeding disorders (Table 1) should be collected
before starting any therapy.
Atraumatic
venipuncture, to avoid excessive activation of
haemostasis and local consumption of platelets,
is required together with appropriate sample
handling and submission.
Table 1: Laboratory Investigation of Bleeding Disorders
Haemostatic
Stage
Screening Test
Component Evaluated
Primary
Haemostasis
Platelet count (in-house estimation
from a blood smear*)
Buccal mucosal bleeding time
(BMBT)*
Activated clotting time (ACT)*
Platelet number
Activated partial thromboplastin
time (APTT)
Prothrombin time (PT)
Thrombin time (TT)
Intrinsic & common pathways
but more sensitive than ACT
Extrinsic & common pathways
Common pathway, quantifies
fibrinogen levels
* Tests which can be performed in-house.
Platelet Count Estimation
Automated cell counting machines can struggle
to count feline platelets, as described in the talk
on Thrombocytopenia. Any thrombocytopenia
should be confirmed by examination of a blood
smear.
BMBT
Since vessel wall disorders are quite rare, a
BMBT in a cat with a normal platelet count is
usually a test of platelet function. In cats with
coagulation defects the BMBT is usually normal,
but rebleeding may occur. A BMBT is carried
out under heavy sedation or general anaesthesia
using a spring-loaded bleeding time device which
makes a pair of standardized incisions in the
mucosa. Normal BMBT in cats is <3.3minutes.
ACT
Tubes for measurement of ACT are produced
commercially and contain diatomaceous earth to
act as the contact activator. Platelet phospholipid
is still required for coagulation so ACT is prolonged
in severe thrombocytopenia (<10x109/l). Clotting
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Secondary
Haemostasis
Platelet (number and) function,
vessel abnormalities
Intrinsic & common pathways
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factors must be <10% normal to prolong the
ACT. Blood is collected into the tube and the
tube inverted and the time taken for complete clot
formation recorded. Normal ACT in cats at room
temperature is <165 seconds. An ACT is also
available on the I-STAT analyser.
APTT and PT
These are usually carried out by commercial
laboratories using citrated blood (an accurate ratio
of 1:9 sodium citrate:blood is required). Samples
(usually cooled plasma) should be delivered to the
laboratory as soon as possible and samples from
a normal animal may be required as a control.
Clotting times >30% prolonged compared to
controls are considered abnormal. Individual
clotting factors need to be <30% before APTT
or PT are prolonged. Point of care coagulation
instruments (e.g. SCA2000) can determine the
APTT and PT on small amounts of fresh citrated
whole blood. These have been shown to be
reliable in dogs.
The APTT is more sensitive than the ACT and
not dependent on platelets. Since Factor VII (a
vitamin K-dependent factor) has the shortest half
life of all clotting factors, the PT will prolong
before the APTT in cases of vitamin K deficiency
or rodenticide toxicity.
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TT
Not commonly performed but is prolonged in
cases of hypo- or dys-fibrinogenaemia, increased
fibrin degradation product levels or circulating
heparin as it assesses the formation of fibrin in
response to thrombin.
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Specific Factor Assays
Deficiency of specific factors can be identified
by specialist laboratories although this can be
costly. The laboratory should be contacted for
submission requirements before the sample is
taken.
ENCOUNTERED FELINE COAGULOPATHY
DISORDERS
Disorders of Primary Haemostasis
Thrombocytopenia, encountered reasonably
frequently in cats, is discussed in a later lecture.
Inherited thrombocytopathias are rarely described
in cats (Chediak-Higashi syndrome in Persians,
vWD), but hepatic, renal, neoplastic, infectious
(e.g. FIP) diseases, disseminated intravascular
coagulopathy (DIC) and drugs (e.g. aspirin) can
all cause acquired thrombocytopathias.
Disorders of Secondary Haemostasis
Inherited Disorders: The most common inherited
congenital coagulopathy in cats is Factor XII
(Hageman) deficiency (Brooks and DeWilde
2006). It is an autosomal recessive disorder
(affecting both males and females) that delays in
vitro activation of the APTT and ACT, causing
these to be prolonged (often markedly), but does
not result in bleeding in vivo. It has been reported
in the DSH, DLH and other breeds including
Siamese and Himalayan. Definitive diagnosis
rests on measurement of Factor XII activity. No
treatment is required.
Haemophilia A (Factor VIII deficiency) and
Haemophilia B (Factor IX deficiency) are sexlinked autosomal recessive (affecting males
only) traits. In a recent study (Brooks and
DeWilde 2006) Haemophilia A and B were both
diagnosed in young cats (<1year) and were found
predominantly in DSH cats, although other breeds
have been affected e.g. Birman, Himalayan. All
haemophilic cats in this report had factor activities
of <5% of feline standard plasma and had shown
signs of bleeding: subcutaneous or intramuscular
haematomas, prolonged bleeding after neutering
and gingival bleeding from teeth eruption sites.
Haemophilic bleeding tendencies vary depending
on the factor activity present. Coagulation testing
reveals prolongation of the ACT and APTT,
although these (especially ACT) can be normal
if the factor deficiency is not severe. Definitive
diagnosis depends on measurement of Factor
VIII or IX activity.
Other inherited coagulopathies reported in cats
include combined Haemophilia A or B and
Hageman trait, Factor XI deficiency, and Factor I
(fibrinogen) ± XI deficiency in Maine Coons.
Treatment of factor deficiencies involves
replacement of the factors required. Fresh
whole blood transfusions are useful if anaemia
is present. Fresh (within 6 hours of collection)
frozen plasma contains active factors. Bleeding
cats should not be given intramuscular injections.
Avoidance of drugs with can impair haemostasis
is also important together with maintaining an
atraumatic life. Breeding should be avoided.
A hereditary vitamin K-responsive coagulopathy
in Devon Rex cats is associated with moderate
to marked decreases in the activity of Factors
II, VII, IX and X due to a defective vitamin K
metabolism enzyme. It affects both males and
females resulting in haematomas, haemarthrosis
and body cavity bleeding. APTT and PT are
markedly prolonged. These cases respond to oral
vitamin K1 at 5mg/kg/d.
Acquired Disorders: Liver disease is an important
cause of acquired coagulopathies in cats (Center,
et al 2000, Lisciandro, et al 1998) since the liver
synthesises clotting factors. Coagulopathies
can also arise in cholestatic liver disease in
which absorption of the fat soluble vitamin K is
impaired due to biliary stasis. Multiple abnormal
coagulation times can occur including prolonged
PT and APTT. Although abnormal coagulation
times are common with liver disease, clinical
signs of spontaneous bleeding are rare. Vitamin
K1 is helpful (0.5mg/kg SQ BID 2-3 times prior
to e.g. surgery, and every 7-21days thereafter) to
correct the PT and APTT. Hepatic lipidosis and
severe cholangiohepatitis cases can respond well
to vitamin K1 (Center, et al 2000).
Vitamin K deficiency also arises due to rodenticide
toxicity, although this is less common in cats than
dogs (Kohn, et al 2003). Cases present with
lethargy, inappetance, haematomas, dyspnoea
due to thoracic haemorrhage and/or collapse.
The PT prolongs before the APTT. Mild
thrombocytopenia may be present. Treatment
comprises vitamin K1 (2.5mg/kg SQ 1st day then
0.25-2.5mg/kg PO in divided doses) for at least
a week (up to 6weeks), with monitoring of the
PT 24 hours after stopping treatment to dictate
whether further treatment is required.
Vitamin K-responsive coagulopathies have
been reported in cats with malabsorption due
to inflammatory bowel disease or exocrine
pancreatic insufficiency.
Methimazole, used in the treatment of
hyperthyroidism, has been reported to affect
activation of vitamin K-dependent factors
although one retrospective study found evidence
to support this in only one of 20 methimazoletreated cats (Randolph, et al 2000).
DIC arises due to the systemic activation of
haemostasis as a result of underlying disease
processes in the body. Platelets and factors
are involved in widespread clot formation
and fibrinolysis is activated. This results in a
thrombocytopenia, factor depletion (prolonged
PT and APTT), low antithrombin, and increased
D-dimers from breakdown of cross-linked
fibrin. Cases present with haemorrhage and/
or thrombosis. In cats DIC is most commonly
associated with neoplasia, liver disease and FIP
(Peterson, et al 1995).
FIV infection has been associated with
prolongation of the APTT due to an intrinsic
pathway problem although the cause of this has
not been identified (Hart and Nolte 1994).
REFERENCES
Brooks, M. & DeWilde, L. (2006) Feline Factor
XII Deficiency. Compendium on Continuing
Education for the Practicing Veterinarian, 28,
148-155.
Center, S.A., Warner, K., Corbett, J., Randolph,
J.F. & Erb, H.N. (2000) Proteins invoked by
vitamin K absence and clotting times in clinically
ill cats. Journal of Veterinary Internal Medicine,
14, 292-297.
Hart, S.W. & Nolte, I. (1994) Hemostatic disorders
in feline immunodeficiency virus-seropositive
cats. Journal of Veterinary Internal Medicine, 8,
355-362.
Kohn, B., Weingart, C. & Giger, U. (2003)
Haemorrhage in seven cats with suspected
anticoagulant rodenticide intoxication. Journal
of Feline Medicine and Surgery, 5, 295-304.
Lisciandro, S.C., Hohenhaus, A. & Brooks, M.
(1998) Coagulation abnormalities in 22 cats
with naturally occurring liver disease. Journal of
Veterinary Internal Medicine, 12, 71-75.
Peterson, J.L., Couto, C.G. & Wellman,
M.L. (1995) Hemostatic disorders in cats: a
retrospective study and review of the literature.
Journal of Veterinary Internal Medicine, 9, 298303.
Randolph, J.F., DeMarco, J., Center, S.A.,
Kantrowitz, L., Crawford, M.A., Scarlett, J.M. &
Brooks, M. (2000) Prothrombin, activated partial
thromboplastin, and proteins induced by vitamin
K absence or antagonists clotting times in 20
hyperthyroid cats before and after methimazole
treatment. Journal of Veterinary Internal
Medicine, 14, 56-59.
Stokol, T. (2005) Disorders of haemostasis. In:
BSAVA Manual of Canine and Feline Clinical
Pathology (ed. by E. Villiers & L. Blackwood),
pp. 83-98. BSAVA, Gloucester.
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