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Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 57 Hemophilia A in a Male Parson Russell Terrier Puppy
Hemophilia A in a Male Parson Russell Terrier Puppy
Aroch, I.,*
1
Tamarin, I.
2
and Kuzi, S.
1
1
Hebrew University Veterinary Teaching Hospital and Koret School of Veterinary Medicine, Hebrew University of Jerusalem,
P.O. Box 12, Rehovot, 761001, Israel.
2
Laboratory of Hemostasis, Institute of Trombosis and Hemostasis, and the National Hemophilia Center, Chaim Sheba
Medical Center, Israel.
*
Corresponding Author: Dr. Itamar Aroch, DVM, DECVIM-CA (Internal Medicine), Koret School of Veterinary Medicine, Hebrew University of
Jerusalem, P.O. Box 12, Rehovot, 761001, Israel. Tel: 03- 9688556, Fax: 03-9604079. E-mail: itamar.aroch@mail.huji.ac.il
ABSTRACT
Hemophilia A (HA) is the most common inherited bleeding disorder in dogs. It is sex-linked, and has been
described in many breeds. Tis report describes the clinical course and the diagnosis of HA in a 7-month old
Parson Russell Terrier puppy, which was presented due to repeated bleeding episodes. Te diagnostic tests
included complete blood counts, prothrombin time (PT), activated partial thromboplastin time (aPTT),
buccal mucosal bleeding time (BMBT), thromboelstometry using a surface contact activator (INTEM) and
tissue factor (EXTEM) and determination of activities of factors VIII, IX and XI. Te platelet counts, BMBT,
PT and EXTEM were within reference intervals. Te activities of factors VIII, IX and XI were 0.97%, 71.0%
and 84.4%, respectively, compared to their average activities in the samples of two healthy dogs. Testing also
ruled out the presence of coagulation inhibitors. Te results confrmed a diagnosis of inherited HA, with severe
factor VIII:C defciency (<1% compared to reference plasmas). Te aPTT, measured both by coagulometric
analyzers and a fbrometer were prolonged (1.05- to 2.3-fold the upper reference limits [URL]), as was the
INTEM clotting time (2.3-fold the URL), and did not refect the severity of the defciency. Te dog was
treated with oral tranexamic acid, which failed to prevent repeating bleeding episodes, and was therefore
euthanized at his owners’ request. Tis is the frst report of HA in a Parson Russell Terrier in Israel, and the
frst report in which thromboelastomtry was also utilized as a diagnostic test in HA in dogs.
Keywords: Canine; Coagulation; Hemostasis; Tromboelastometry; Factor VIII;
Tranexamic Acid
INTRODUCTION
Hemophilia A (HA) is a hereditary, recessive, sex-linked
bleeding disorder, almost exclusively afecting males, resulting
from of a functional or quantitative factor VIII:C (FVIII:C)
defciency. Te latter is a non-enzymatic protein, a crucial
coenzyme for factor IXa, a serine protease, and together they
form the intrinsic tenase, an important procoagulant com-
plex, responsible for factor Xa generation, and subsequently
conversion of prothrombin to active thrombin (1).
Te disease is well described in humans, with over 2300
documented unique mutations in the factor VIII:C gene-
encoding (2, 3), however, limited information regarding such
mutations is known in dogs (4, 5). It is the most common
hereditary secondary clotting disorder in dogs, and may afect
any dog breed (1, 6). It has been described in several dog
breeds, including mixed breeds (mostly German Shepherd
and Labrador retriever crosses), German Shepherd, Labrador
and Golden retrievers, Boxer, Belgian Mallinois, Cocker
Spaniel, Weimaraner, Miniature Poodle, American Pit Bull
Terrier, Beagle, Dachshunds and Dachshund crosses, Parson
Russell Terrier (also known as Jack Russell Terrier) and its
crosses, West Highland White Terrier, German Shorthaired
Case Reports
Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 Aroch, I. 58
Pointer, Australian Kelpie, Bassett Hound, Boston Terrier,
Chihuahua, Chow-Chow, English Bulldog, Japanese Chin,
Miniature Schnauzer, Pug-Beagle crossbred, Redbone
Coonhound, Rhodesian Ridgeback, Rough Collie, Saint
Bernard, Shih Tzu, Yorkshire Terrier, and Welsh Corgi (1,
6, 7-14). Based on the human criteria, in the largest survey
study of the disease (n = 39), the severity of HA, based on
FVIII:C defciency, was mild (FVIII:C activity 6%-20% of
the RI), moderate (2%-5%) and severe (<2%) FVIII:C def-
ciencies were recorded in 10, 13 and 16 dogs, respectively (7).
In most dogs with HA, the disease is diagnosed within
one year of age, and all are diagnosed within 25 months. Te
initial clinical signs of HA mostly include spontaneous bruis-
ing or hematomas (38%), as well as excessive or unanticipated
bleeding during elective surgical procedures, gingival bleeding
during loss of deciduous teeth, bleeding after minor trauma,
and spontaneous intra-cavity or organ bleeding, hematoche-
zia, hematemesis, scleral hemorrhage and epistaxis. Te most
common bleeding sites are the subcutaneous tissue (67%),
joints (51%) and gums (36%) (1, 6, 7).
Te fnal diagnosis of HA is based on demonstrating
FVIII:C defciency as measured by activated partial throm-
boplastin time (aPTT), in which a 1:1 mixture of the suspect
dog plasma and a commercial FVIII:C-defcient plasma is
checked, compared to a similar mixture of a plasma pool,
or plasma of normal healthy controls with the commercial
FVIII:C-defcient plasma (6, 15).
CASE REPORT
A 7-month old, male pure-bred Parson Russell terrier, pur-
chased from a breeder, was referred to the Hebrew University
Veterinary Teaching Hospital (HUVTH) due to repeating
bleeding episodes. Two months prior to presentation, a hema-
toma of 10-cm diameter was observed by the owners on the
head after the dog had sufered from a minor trauma to the
head. Te hematoma was aspirated by the referring veterinar-
ian, but recurred a day later, and was then left untreated,
and resorbed within several days. One month later, with
teething, profound bleeding was noted by the owners from
the deciduous canine teeth, for four days, and melena was
noted as well. A complete blood count (CBC) showed a re-
generative anemia (hematocrit 21.3%, reference interval [RI]
37.3-61.7%; reticulocytes 249x10
3
/µL, RI 10-110x10
3
/µL).
Te platelet count was 204x10
3
/µL (RI 148-484x10
3
/µL).
Te prothrombin time (PT) was 12.2 sec (compared to 11.1
sec of a plasma pool). Te activated partial thromboplastin
time was 40 sec (compared to 20.1 sec of a plasma pool). Te
deciduous tooth where the bleeding was noted was extracted.
Te dog was prescribed omeprazole (10 mg PO q12h) and
sucralfate (0.5 g PO q8h), due to suspected gastrointestinal
bleeding, tranexamic acid (TXA; hexakapron, Teva, Petach-
Tikva, Israel; 125 mg PO q12h, approximately 18 mg/kg) and
oral ferrous-sulfate (dose and brand unknown). One month
later, the dog was rechecked, and was without any abnor-
malities. Omeprazole and sucralfate were discontinued. Two
days later, the dog was rechecked and seemed normal, and
all medications were discontinued. Two days later, the dog
was presented to the Hebrew University Veterinary Teaching
Hospital (HUVTH). Physical examination was unremark-
able. A CBC showed a mild macrocytic anemia (hematocrit
35.7%, RI 37.1-57%; mean corpuscular volume [MCV] 79.7
fL, RI 58.8-71.2 fL), and the platelet count was within the
RI. Blood smear examination showed mild polychromasia,
anisocytosis, hypochromasia and schistocytosis.
Coagulation times were frst performed using an auto-
mated coagulometric analyzer (ACL-9000, Instrumental
Laboratories, Milano, Italy). Te PT was 11.1 sec (RI
6.0-9.0 sec), the aPTT was 20.4 sec (RI 11.5-19.5 sec)
and fbrinogen concentration was 277 mg/dL (RI 150-300
mg/dL). Te aPTT was repeated, and was 20.9 sec. Buccal
mucosal bleeding time (BMBT) was 3 min and 20 sec (RI
1.7-4.2 min). Tromboelastometry (Rotem GmbH, Munich,
Germany) was performed twice, once using a contact activa-
tor (INTEM) and once with tissue factor (TF) (EXTEM).
Te latter was unremarkable. Te INTEM (Figure 1) showed
a markedly prolonged clotting time (CT; 459 sec, RI 31-97
sec), while the maximal clot force (MCF) was mildly in-
creased (75 mm, RI 42-70 mm), as were clot forces at 10 and
20 min (A10 and A20, respectively; (Figure 1). Te INTEM
maximal lysis (ML) was increased (27%, RI 0-17%) as were
the time to maximal velocity (MAXV-t), maximal clot elas-
ticity (MCE) and the area under the curve (AUC) (Figure
1). Based on the historical bleeding episodes, the normal
PT, BMBT and EXTEM, the markedly prolonged INTEM
CFT and the prolonged aPTT as measured at the refer-
ring clinic, and despite the repeated automatically measured
aPTTs at the HUVTH, which were only mildly prolonged,
an inherited defciency in one of the intrinsic coagulation
Case Reports
Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 59 Hemophilia A in a Male Parson Russell Terrier Puppy
pathway factors, VIII:C, IX or XI, (hemophilia A, B and C,
respectively) was suspected.
Te aPTT was then measured twice using a fbrometer
(KC-1 micro, Amelung, Lemgo, Germany), and results
were 44.9 and 35.8 sec (RI 11.5-19.5 sec.). Plasma from
the dog was then mixed 1:1 with citrated plasma obtained
from a healthy staf-owned dog (in which the aPTT was
17.2 sec.), and the aPTT was repeated, using both the
automated coagulometric analyzer and the fbrometer, and
results were 15.9 and 20.5 sec., respectively. Tis confrmed
that no coagulation inhibitors were present in the suspect
dog’s plasma which potentially might have led to prolonged
aPTT.
Te dog was discharged with oral TXA (125 mg q8h)
treatment pending further tests. Two days later, the dog was
represented to the HUVTH due to a large hematoma, of
10-cm in diameter in the jugular area, where the venipuncture
was made in order to obtain blood samples during the prior
visit. At that time, the packed cell volume was 40%, and the
fbrometer aPTT was 41.7 sec.
Frozen citrated plasma from the suspect dog and from
two healthy staf-owned dogs (in which the aPTTs were
within RI) that were used as reference samples, were sent
to the Laboratory of Hemostasis, Institute of Trombosis
and Hemostasis, Chaim Sheba Medical Center, Israel, for
measurement of coagulation factors VIII, IX and XI activi-
ties. Factor VIII, IX and IX activity levels in dog's plasma
were measured by ACL TOP 500 analyzer (Instrumental
Laboratories, Bedford, MA. USA), using SynthASil and
factor VIII-defcient plasma, factor IX-defcient plasma
and factor XI-defcient plasma, respectively (HemosIL,
Instrumental Laboratories, Bedford, MA. USA).Te activi-
ties of factors VIII, IX and XI of the dog were 0.97%, 71.0%
and 84.4%, respectively, compared to their average activities
in the samples of the two healthy dogs, thereby confrming
presence of severe FVIII:C defciency (HA).Te owners
were instructed to avoid strenuous activity, and TXA was
prescribed.
Two weeks later, the dog swallowed a plastic bag, and was
administered apomorphine intramuscularly by the referring
veterinarian, and subsequently developed a large hematoma at
the injection site. Te dog was then euthanized at his owners’
Figure 1: Tromboelastogram of a Parson Russell Terrier puppy with hemophilia A, using a contact activator (INTEM). Numeric data are
presented on the right hand side, with reference intervals in parentheses. CT, clotting time; CFT, clot formation time; α, alpha angle; A10, clot
force at 10 min.; A20, clot force at 20 min.; MCF, maximal clot force; ML, maximal lysis; LI30, LI45 and LI60, clot lysis at 30, 45 and 60 min.,
respectively; MAXV, maximal velocity; MAXV-t, time to maximal velocity; AUC, area under the curve; MCE, maximal clot elasticity; MCF-t,
time to maximal clot force; CFR, clot formation rate; LOT, lysis onset time.
Case Reports
Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 Aroch, I. 60
request. Te breeder was notifed, but further inquiry was
declined.
DISCUSSION
Te present dog was suspected with an inherited coagu-
lopathy based on its male sex and the typical clinical signs
of repeated bleeding episodes, which have occurred when
the dog was aged less than seven months, appeared at veni-
puncture sites, teething sites and one suspected bruising site,
in agreement with previous reports of canine HA (1, 6, 7).
Hemophilia A has been reported previously in the Parson
Russell Terrier (7), but this is the frst report of the disease
in this breed in Israel. HA occurs on average in 50% of the
males in a litter, while 50% of its females will be carriers,
by breeding a carrier female with an afected male. Males
with mild forms of hemophilia may survive to reproduce, and
when bred, the mutation is transmitted to all his daughters,
which will be carriers, but none of his sons will be afected
(1). A full inquiry as to the dame, sire and littermates was
warranted in this case. Since Parson Russell Terriers are be-
coming more popular in the country and because inbreeding
may occur, local veterinarians and breeders should be aware
of the possibility of occurrence of HA in the breed.
CBCs, performed at both the referring clinic and the
HUVTH ruled out thrombocytopenia, while the BMBT
ruled out thrombopathy. In addition, the PT results at
both the referring clinic and the HUVTH, although very
mildly prolonged compared to their RI (or compared to a
plasma pool at the referring clinic), could not account for
the repeating bleeding episodes in this dog, and ruled out
inherited factor VII defciency or common coagulation
pathway clotting factor defciency. Fibrinogen (Clauss) con-
centration was within RI, ruling out hypofbrinogenemia or
dysfbrinogenemia. While the aPTT, measured by automatic
coagulometric analyzers at both the referring clinic and at the
HUVTH were prolonged, this prolongation was only 1.046
to 2-fold the upper reference limit (URL) (or compared to
a plasma pool at the referring clinic), and did not refect a
severe inherited coagulopathy. Similarly, the aPTT measured
by a fbrometer at the HUVTH, although prolonged, was
only 1.84- to 2.30-fold the URL. It was therefore uncertain,
based on these results, that hemophilia was indeed likely.
A previous study has examined the relationship between
the aPTT and FVIII:C concentration in 145 samples from
dogs with HA, and showed that although the correlation
between the two was highly signifcant, the relationship
could be proven most precisely by geometric regression, and
not by a linear correlation (16). In other words, in a single
hemophiliac dog, although plasma FVIII:C activity might
be markedly low, the aPTT prolongation might not refect
it precisely in a linear manner. Tis might explain the mildly,
unremarkably prolonged aPTTs in this case, although plasma
FVIII:C activity was subsequently shown to be markedly low
(<1% compared to healthy controls), and therefore supporting
a severe form of HA.
In agreement with unremarkable prolongation of the
aPTT, the thromboelastometry INTEM test did show a
similar prolongation of the CT, which was 2.3-fold the URL,
and the MAXV-t was 2-fold the URL as well. Interestingly,
the INTEM measures of clot strength, (A10, A20 and MCF)
as well as the MCE were mildly above their RI. Te reason
is unclear, and since these measurements were very near the
URL in the EXTEM test, the clinical signifcance of these
abnormalities is questionable. Tey might suggest that once
formed, the clot force is adequate. Tis is supported by the
increased AUC as well. Te reason for the increased INTEM
ML is unclear, but this was a mild increase, and it signifcance
is questionable as well. Both the INTEM and EXTEM dem-
onstrated that global coagulation was normal in the dog,
excluding the prolonged INTEM CT. Tromboelastometry
or thromboelastography test results have never been reported
in dogs with HA, to our best knowledge, and this is the frst
repot to do so. In hemophiliac humans, these tests are mostly
utilized for monitoring individual patients during therapy,
especially when inhibitors of coagulation are identifed (17,
18), but we could not fnd evidence of such tests to be used
in screening of humans with HA.
In human hemophiliacs, historical treatments included
fresh frozen plasma (FFP), and later on, cryoprecipitate,
which were later substituted with factor replacement therapy,
frst with virally-inactivated FVIII concentrates, and current-
ly with several human recombinant FVIII products, or with
bypass therapy (19-21). FVIII concentrates, recombinant
FVIII and bypassing agents (i.e., recombinant factor VIIa
and activated prothrombin complex concentrate [APCC]) are
administered both for prophylaxis as and control of bleeding.
Tese are unavailable for treatment of dogs, generally because
such treatment is cost-prohibitive. Additionally, potentially,
such treatment might result in development of anti-FVIII
Case Reports
Israel Journal of Veterinary Medicine  Vol. 70 (4)  December 2015 61 Hemophilia A in a Male Parson Russell Terrier Puppy
(or anti-factor VIIa) antibodies, which will result in bleed-
ing. Cryoprecipitate is also mostly unavailable in veterinary
medicine due to cost issues. Terefore, similar prophylaxis is
not practiced in hemophiliac dogs, while treatment of bleed-
ing is limited to FFP, whole blood and packed cells (7). Most
dogs with HA sufer repeated bleeding episodes, and the
main treatments reported included transfusion of FFP, whole
blood and packed cells. In a survey of hemophilia A in 39
dogs, most dogs (56%) required a single transfusion or single
yearly transfusions, and the rest received several transfusions.
FFP was the most commonly used blood product (n = 22).
Tirty-fve dogs of these 39 dogs were treated, for up to
eight years post-diagnosis, while four were euthanized at
the time of the diagnosis or shortly thereafter. Of these 35
dogs, seven were subsequently euthanized due to the disease,
fve died due to bleeding, resulting from FVIII:C defciency,
while 18 were still alive and being treated at the time the
survey was conducted (7). Treatment of dogs is therefore
expensive, requiring long-term owner commitment, while
the long-term prognosis must be guarded. In the present
dog, due to several bleeding episodes over a relatively short
time-period, and in light of the severe FVIII:C defciency, the
owners elected euthanasia, although the possibility that the
dog could survive for a relatively long period was conveyed
to them. In a previous survey of HA in dogs, 4/39 dogs
were euthanized at the time the diagnosis of the disease was
made (7). While the election of euthanasia in the present
dog might be argued, since in this case FVIII defciency was
severe, repeated bleeding episodes were to be expected. In
the above mentioned survey (7), 13/39 cases were defned as
severe FVIIIa defciency. Among these, 2 dogs were lost to
follow-up. Four dogs of the remaining 11 cases (36%) were
either euthanized or died within two years from the time the
diagnosis of HA was made (7).
Tere are no reports on the use of TXA in dogs with HA,
although it has been investigated in healthy dogs, and was
found to be safe (27). In hemophiliac humans with coagula-
tion factor inhibitors, addition of TXA to treatment with
recombinant human factor VIIa (rhFVIIa) or with APCC,
resulted in clot stability normalization compared to healthy
controls (22). Good to excellent results were achieved in 9/10
human HA patients undergoing surgery, or with bleeding,
with bypassing agent (i.e., use of rhFVIIa or APCC which
promote coagulation and ‘bypass’ the intrinsic coagulation
pathway) and TXA treatment (23). Similar results were dem-
onstrated by thromboelstometry in vitro (24). Te potential
of TXA as a prophylactic agent against bleeding in hereditary
coagulation disorders in human patients untreated with factor
replacement or bypassing agent (i.e., rhFVIIa or APCC)
therapy undergoing endoscopy was safe and benefcial in
cases of mild to moderate coagulation disorders (25). Pre-
and post-operatively administered TXA has also been used
successfully with a single recombinant factor VIIa in prevent-
ing bleeding in humans with severe factor IX defciency and
inhibitors undergoing major surgeries (26).
To the best of the knowledge of the authors, there are
no studies of TXA as a sole prophylactic agent in non-
symptomatic hemophiliac humans. In an uncontrolled
retrospective study comparing the use of blood products in
dogs with various, non-hemophilia bleeding disorders, it was
concluded that TXA is safe, but there were no conclusive
evidence as to it efciency in reducing blood product transfu-
sion requirements (27). In another study, evaluating the efect
of intravenous TXA in healthy dogs on thromboelstographic
measures, the results were unremarkable (28). In the present
dog, no bleeding episodes were noted throughout the initial
period in which the dog had been treated with TXA. When
the venipuncture was made at the HUVTH the dog was not
receiving any medications, and the procedure resulted in a
hematoma in the jugular vein area. Te dog was discharged
later from the hospital with TXA treatment. However, de-
spite this ongoing treatment, he developed a hematoma at
an injection site later on. It is therefore impossible to draw
any conclusion as to the efect of TXA treatment in this case.
It was minor at best, or possibly, the drug had no benefcial
efect. It would seem that with no additional bypassing agent
or FVIII:C replacement therapy, oral TXA cannot prevent
bleeding associated with minimally invasive procedures, such
as venipuncture, in dogs.
In conclusion, this is the frst report of HA in a pure-
bred Parson Russell Terrier in Israel, and, to the best of our
knowledge the frst report of thromboelastometry measures
in a naturally-occurring HA in dogs. Treatment with TXA
failed to prevent bleeding in this case.
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Case Reports