Received: 7 December 2018 Accepted: 8 December 2018

DOI: 10.1111/vec.12797

SPECIAL ARTICLE

Consensus on the Rational Use of Antithrombotics in

Veterinary Critical Care (CURATIVE): Domain 1—Defining
populations at risk
Armelle deLaforcade DVM, DACVECC1 Lenore Bacek DVM, MS, DACVECC2 ∗
Marie-Claude Blais DVM, DACVIM3 ∗ Robert Goggs BVSc, DACVECC, DECVECC,
PhD4 ∗ Alex Lynch BVSc (Hons), DACVECC5 ∗ Elizabeth Rozanski DVM, DACVIM,
DACVECC1 ∗

1 Department of Clinical Sciences, Cummings

School of Veterinary Medicine at Tufts Univer- Abstract

sity, North Grafton, MA Objectives: Thrombosis is a well-recognized phenomenon in dogs and cats with a significant
2 Department of Clinical Sciences, College of Vet-
impact on morbidity and mortality. Despite growing awareness of thrombosis and increased use
erinary Medicine, Auburn University, Auburn, of antithrombotic therapy, there is little information in the veterinary literature to guide the use of
AL
anticoagulant and antiplatelet medications. The goal of Domain 1 was to explore the association
3 Department of Clinical Sciences, University of

Montreal, Saint-Hyacinthe, QC, Canada

4 Department of Clinical Sciences, Cornell Uni-
versity College of Veterinary Medicine, Ithaca,
NY
5 Department of Clinical Sciences, NC State
College of Veterinary Medicine, Raleigh, NC
Correspondence
Dr. Armelle deLaforcade, Small Animal Emer-
gency and Critical Care, Cummings School of
Veterinary Medicine at Tufts University, 200
Westboro Road, North Grafton, MA 01536.
Email: Armelle.delaforcade@tufts.edu
∗ These authors contributed equally to this
between disease and thrombosis in a number of conditions identified as potential risk factors in
the current veterinary literature, to provide the basis for prescribing recommendations.
Design: A population exposure comparison outcome format was used to represent patient, expo-
sure, comparison, and outcome. Population Exposure Comparison Outcome questions were dis-
tributed to worksheet authors who performed comprehensive searches, summarized the evi-
dence, and created guideline recommendations that were reviewed by domain chairs. Revised
guidelines then underwent the Delphi survey process to reach consensus on the final guidelines.
Diseases evaluated included immune-mediated hemolytic anemia, protein-losing nephropathy,
pancreatitis, glucocorticoid therapy, hyperadrenocorticism, neoplasia, sepsis, cerebrovascular dis-
ease, and cardiac disease.

manuscript.
Settings: Academic and referral veterinary medical centers.

Funding information
Funding for this work was provided by the Ameri-
can College of Veterinary Emergency and Critical
Care (ACVECC) and the Veterinary Emergency
and Critical Care Society (VECCS)
Prior presentation: This work was presented in
part at the European Veterinary Emergency and
Critical Care Congress, June 2018, Venice, Italy,
and at the International Veterinary Emergency
and Critical Care Symposium, September 2018,
New Orleans, LA.
Results: Of the diseases evaluated, a high risk for thrombosis was defined as dogs with immune-
mediated hemolytic anemia or protein-losing nephropathy, cats with cardiomyopathy and associ-
ated risk factors, or dogs/cats with >1 disease or risk factor for thrombosis. Low or moderate risk
for thrombosis was defined as dogs or cats with a single risk factor or disease, or dogs or cats with
known risk factor conditions that are likely to resolve in days to weeks following treatment.
Conclusions: Documented disease associations with thrombosis provide the basis for recommen-
dations on prescribing provided in subsequent domains. Numerous knowledge gaps were identi-
fied that represent opportunities for future study.

KEYWORDS
cardiomyopathy, IMHA, PLN, thromboembolism, thrombosis

INTRODUCTION

Thrombosis is a well-recognized cause of morbidity and mortality in

Abbreviations: ATE, aortic thromboembolism; CT, computed tomography; HAC,
hyperadrenocorticism; HCM, hypertrophic cardiomyopathy; IMHA, immune-mediated
people, with large studies documenting reduced risk of thrombotic
hemolytic anemia; LA, left atrial; LOE, level of evidence; PECO, population exposure complications with institution of anticoagulant therapy.1–3 Despite
comparison outcome; PLN, protein-losing nephropathy; PTE, pulmonary thromboembolism;
growing awareness of thrombosis as a manifestation of disease in
TEG, thromboelastography; VTE, venous thromboembolism

J Vet Emerg Crit Care. 2019;29:37–48. wileyonlinelibrary.com/journal/vec 

c Veterinary Emergency and Critical Care Society 2019 37
38 DELAFORCADE ET AL.

veterinary medicine, few large studies quantifying risk are available to Evidence summary
inform decisions related to anticoagulation leading to inconsistent and
While not directly addressing the question due to their retrospec-
anecdotal application of antithrombotic therapy. The predominance
tive nature and lack of controls (level of evidence [LOE] 5, Good), 3
of deep vein thrombosis as a precursor to pulmonary embolism in
studies provide the most compelling evidence that thrombosis is an
people and of atherosclerosis as a precursor to arterial thrombosis
important complication of IMHA. In the Klein study, 31 dogs diag-
further complicates our ability to directly extrapolate from the human
nosed with IMHA in a 5-year period had necropsies performed. Of
literature, given that deep vein thrombosis and atherosclerosis are
these, 10 dogs developed fatal pulmonary thromboembolism (PTE),
uncommon in veterinary medicine. Growing interest in hypercoagu-
and 2 of the 10 dogs had multiorgan evidence of thrombosis.27 The
lability has led to the development of a body of veterinary literature
second study of 34 dogs with IMHA that had a necropsy found
describing thrombosis and use of antithrombotics in dogs and
that 25 dogs (73.5%) had evidence of coagulopathy in the form of
cats.4–13
macrothrombosis, microthrombosis, widespread fibrin deposition, and
Retrospective studies of thrombotic states consistently docu-
hemorrhage. In addition to pulmonary thrombi, splenic renal and car-
ment a number of comorbidities that likely represent hypercoag-
diac infarction was commonly noted.28 A third study of 72 dogs with
ulable states.5,7,14–26 The lack of large epidemiology studies that
IMHA noted thromboembolism in 20 of 25 dogs that had postmortem
quantify risk of thrombosis with any one disease state compli-
examinations.29 A small, prospective but uncontrolled study (LOE 5,
cates generation of recommendations related to antithrombotic
Good) evaluated 12 dogs with IMHA and respiratory distress using
therapy. Despite this, an expanding understanding of physiologic
computed tomographic (CT) pulmonary angiography.30 The CT pul-
conditions favoring thrombus formation, combined with known
monary angiography studies confirmed PTE in 3 dogs and were con-
comorbidities and existing veterinary studies, allows for reasonable
sistent with PTE in a further 3 dogs.
determination of the strength of association between disease and
A hypercoagulable state associated with IMHA is supported by a
thrombosis.
number of studies seeking to determine the underlying mechanism
The goal of Domain 1 was to explore the association between dis-
of altered hemostasis in this disease. A series of prospective con-
ease and thrombosis in a number of conditions identified as potential
trolled investigations (LOE 2, Good) identify increased tissue factor
risk factors in the current veterinary literature, to provide the basis
expression,31 platelet activation,32,33 procoagulant microparticles,34
for recommendations on prescribing documented in the subsequent
and neutrophil extracellular traps,35,36 in dogs with IMHA compared
domains. A standardized Population Exposure Comparison Outcome
to controls. Conversely, antiphospholipid antibodies were not impli-
(PECO) question format was used to investigate whether in dogs or
cated as a potential cause for thrombosis in dogs (LOE 2, Good).37
cats (Population, P), the development of a disease (Exposure, E), as
Four additional studies used thromboelastography (TEG) to assess
opposed to remaining disease free (Comparison, C), was associated
the whole blood coagulation status in dogs with IMHA. Of these, 1
with the development of thrombosis (Outcome, O). Risk for thrombo-
study (LOE 2, Good) sampled dogs prior to glucocorticoid administra-
sis was further classified as "high," "moderate," or "low." A designation
tion, thus removing the confounding factor from analysis.38 The other
of high risk was used for those diseases with clear and consistent evi-
prospective study (LOE 2, Fair) performed serial evaluations using TEG
dence for thrombosis as a complication of disease, and for dogs and
but enrolled dogs that had received glucocorticoids no more than 3
cats with multiple risk factors. A designation of low or moderate risk
days prior to enrollment.39 The remaining 2 studies were retrospec-
was used for dogs and cats with a single risk factor or disease, where
tive in nature with no controls (LOE 5, Poor) and included dogs that
the degree of association with thrombosis was demonstrably lower,
had received glucocorticoids.40,41 All 4 of these studies documented
and for dogs or cats with known risk factor conditions that, with treat-
changes consistent with hypercoagulability on TEG, and in 2 studies,
ment, are likely to resolve in days to weeks.
the lack of hypercoagulability (relative hypocoagulability) was found to
be a negative prognostic indicator.39,40
Finally, a number of studies involving dogs with IMHA unrelated to
PECO QUESTION: Immune-mediated hemostasis document thrombosis in a significant proportion of dogs
hemolytic anemia that had necropsies performed. It should be noted that a suspicion of
PTE without necropsy confirmation is frequently noted in studies of
In dogs (P), is the development of immune-mediated hemolytic anemia IMHA.42–49 While multiorgan distribution of thrombosis is also iden-
(IMHA) (E), as opposed to remaining disease free (C), associated with tified in IMHA, the pulmonary system seems most prominently repre-
the development of thrombosis (O)? sented in thrombotic complications of this disease.

Guidelines
1.1 Immune-mediated hemolytic anemia (dogs only)
a. Immune-mediated hemolytic anemia (IMHA) is strongly asso-
ciated with the development of thrombosis in dogs.
b. We recommend antithrombotic therapy for dogs with IMHA.
Knowledge gaps
Due to the significant occurrence of thrombosis complicating IMHA,
antithrombotic therapy is warranted. Although there is some literature
describing the use of antithrombotics in IMHA, the number of dogs
included in studies investigating anticoagulation strategies is small and
DELAFORCADE ET AL.
the overall evidence is insufficient to recommend 1 particular strat-
egy over another. Large prospective studies comparing anticoagulant
strategies in dogs with IMHA and their impact on outcome are needed.
PECO QUESTION: Protein-losing
nephropathy
In dogs (P), is the development of protein-losing nephropathy (PLN) (E)
as opposed to remaining disease free (C) associated with the develop-
ment of thrombosis (O)?
Guidelines
1.2 Protein-losing nephropathy (PLN) (dogs only)
a. Protein-losing nephropathy (PLN) is associated with the devel-
opment of thrombosis in dogs.
b. We recommend antithrombotic therapy for dogs with PLN.
Evidence summary
Of 22 studies reviewed, 15 studies (ranging from LOE 2–5, Fair)
support an association between PLN and thrombosis.19,22–25,50–59
Because of the lack of control groups in the majority of these publica-
tions, when evaluated individually a clear cause and effect relationship
between PLN and the development of thrombosis cannot be estab-
lished. However, when evaluated as a whole, the total number of dogs
described with various thrombotic conditions with concomitant PLN
highlights the significance of this disease in pathologic thrombosis.
Similarly, studies investigating hemostatic changes in dogs with
PLN all describe thromboembolic complications in 6% to 42% of
dogs.50–54,56,60–63
Three prospective studies (1 LOE 2, 2 LOE 3) investigate hemostatic
changes in dogs with PLN and all 3 support hypercoagulable changes
in this patient population.50,60,61 All 3 evaluated hemostatic changes
using TEG and antithrombin activity, with 1 including additional hemo-
static proteins. In the only study to include a control population, 29
dogs with PLN, renal failure without proteinuria, and systemic inflam-
mation were compared to 20 healthy controls.50 Hypercoagulability
was documented in all dogs with PLN and renal failure, with no changes
unique to PLN identified (LOE 2, Good). However, 3 of 11 dogs with
PLN experienced thrombosis, and none in the other patient popula-
tions studied.50
Retrospective studies of thrombosis consistently list PLN as an
underlying disease process.16,19,20,22–24,55,63 In a large study of 291
dogs with aortic thromboembolism (ATE), 64 dogs (22%) had an under-
lying disease of PLN (LOE 4, Good).5 This was compared to 16% of
dogs with PLN in the Van Winkle study of 36 dogs with ATE.24 Several
large retrospective studies of dogs with PLN also support a significant
development of thrombosis in this population. When Shar-Pei dogs
were compared to non Shar-Pei dogs in a study of 91 dogs with renal
amyloidosis, thromboembolism was detected postmortem in 13/62
dogs (21%), most being non Shar-Pei dogs. PTE was most frequently
documented followed by aortic thrombosis (LOE 5, Fair).56 Another
39
retrospective study of 52 dogs (LOE 4, Good) with renal amyloidosis
described 20 dogs with thromboembolism (38%) with the most com-
mon location being the pulmonary vasculature.51 In a third study of
222 dogs with familial protein-losing enteropathy and PLN, 10/84
dogs (12%) with PLN developed thromboembolic complications (LOE
5, Good).62 Finally, in 137 dogs with protein-losing glomerular disease,
13% of dogs experienced thromboembolism and this complication was
the second most common cause of death, accounting for 22% of deaths
in this study. The pulmonary vasculature was most commonly affected
(LOE 5, Fair),15,16,51–53,56,57 followed by ATE,5,24,51,52,56,64 but venous
thrombi have also been described.19,22,23,51 Based on these studies, an
association exists between PLN and the development of thrombosis,
with the pulmonary vasculature most commonly affected.
Knowledge gaps
Due to the lack of control groups in most studies of PLN, a clear cause
and effect relationship between this disease and the development of
thrombosis cannot be established. It is possible that additional risk fac-
tors may be present in some of these patients that precipitate a throm-
botic event.
PECO QUESTION: Pancreatitis
In dogs (P), is the development of pancreatitis (E) as opposed to remain-
ing disease free (C) associated with the development of thrombosis
(O)?
Guidelines
1.3 Pancreatitis (dogs only)
a. Severe pancreatitis, in particular acute necrotizing pancreati-
tis, may be associated with the development of thrombosis in
dogs.
b. We suggest that antithrombotic therapy be considered for
dogs with acute pancreatic necrosis, particularly when pro-
thrombotic conditions are present.
Evidence summary
Information regarding the incidence of thrombosis in dogs with pan-
creatitis compared to healthy dogs is lacking. Guideline recommenda-
tions were derived from studies supporting a hypercoagulable state in
dogs with pancreatitis, retrospective studies of dogs with a diagnosis
of pancreatitis, and retrospective studies of thrombotic states in dogs
in which a subset of dogs had underlying pancreatitis.
Three studies suggest that canine pancreatitis is associated with
a hypercoagulable state. Kim et al (LOE 5, Poor) identified reduced
thrombomodulin expression (and hence increased risk of thrombosis)
in liver, lung, and spleen of dogs with systemic inflammation secondary
to septic peritonitis or acute pancreatitis.65 Similarly, Kuzi et al retro-
spectively evaluated 149 dogs in which antithrombin was measured
and found that 13/15 dogs with pancreatitis had reduced antithrom-
40
bin activity placing them at risk for thrombosis (LOE 5, Poor).66 A final
study using a TEG assay modified with tissue plasminogen activator
found decreased fibrinolysis in diseased dogs, with dogs experiencing
systemic inflammation among those experiencing the greatest resis-
tance to fibrinolysis (LOE 2, Poor).67 None of these studies included
dogs with clinical evidence of thrombosis.
A study of 70 dogs with fatal acute pancreatitis identified infarcts
or thrombi on necropsy in 38.5% of dogs compared to 11.5% of con-
trol dogs admitted for trauma (LOE 4, Good).68 Another prospective
study of 10 dogs with suspected pancreatitis undergoing CT angiogra-
phy documented portal vein thrombosis in 3 dogs that were not visual-
ized using ultrasonography (LOE 3, Good).69 However, a fairly large ret-
rospective study of 80 dogs with pancreatitis did not include any dogs
with thrombotic complications (LOE 5, Poor).70
Retrospective studies of thrombotic states listed pancreatitis as the
underlying disease in 2 studies of splenic vein thrombosis (14/80 and
1/16 dogs),22,55 2 studies of ATE (4/36 and 1/9 dogs),24,71 and in 3
studies of portal vein thrombosis (1/33, 1/4, and 4/11 dogs).19,20,63
In 4 of these studies, acute pancreatic necrosis was the histopatho-
logic diagnosis, a potentially relevant finding given that this is also the
type of pancreatitis associated with thrombotic complications in peo-
ple. An additional handful of case reports of dogs experiencing pancre-
atitis and thrombosis support an association between pancreatitis and
thrombosis in dogs (LOE 5, Fair).72,73
Comorbidities were commonly identified in dogs with pancreati-
tis, complicating the assessment of the association between pancre-
atitis and thrombosis. In 1 retrospective study of 80 dogs with splenic
vein thrombosis, all 14 dogs with underlying pancreatitis had at least
1 other concurrent disease process including immune-mediated dis-
ease, neoplasia, diabetes mellitus, or renal disease.22 The contribution
of these additional disease processes to the risk assessment for throm-
bosis in pancreatitis is unknown.
Knowledge gaps
Despite identifying acute pancreatic necrosis as the most com-
mon histopathologic diagnosis in dogs with pancreatitis experiencing
thrombosis, the lack of histopathology in practice with this disease
along with the frequent presence of comorbidities complicates the
ability to make a strong anticoagulation recommendation.
PECO QUESTION: Glucocorticoid
administration
In dogs and cats (P), is glucocorticoid administration (E) as opposed to
remaining drug free (C) associated with the development of thrombosis
(O)?
Guidelines
1.4 Glucocorticoid administration (dogs)
a. Corticosteroid administration favors a hypercoagulable state
in dogs.
DELAFORCADE ET AL.
b. Treatment with corticosteroids may be associated with the
development of thrombosis in dogs, in particular those with
other risk factors for thrombosis.
c. We suggest that antithrombotic therapy be considered for
dogs receiving corticosteroids where other risk factors for
thrombosis exist.
d. There is insufficient evidence to define an association between
corticosteroid administration and development of thrombosis
in cats.
Evidence summary
Dogs
No studies directly investigating the relationship between glucocor-
ticoids and the increased risk of thrombosis in dogs were identified.
The guideline recommendations are derived from studies in healthy
dogs investigating hemostatic changes in dogs following therapy with
oral prednisone,13,74–76 and retrospective studies of thrombotic states
where concurrent or recent therapy with glucocorticoids featured
prominently in dogs experiencing thrombosis.15,16,19,20,22–24,55
Four studies (LOE 3, Fair) prospectively evaluated the impact of
oral prednisone on hemostasis in healthy dogs. Findings including
increased coagulation factors, platelet aggregation, fibrinogen concen-
tration, clot strength, and thrombin generation along with reduced
antithrombin and clot lysis times support a transition to hypercoagula-
ble state with prednisone therapy.13,75–77 The actual risk of thrombo-
sis is unknown, and the relevance of these changes to those that might
occur in a diseased state has not been determined.
While not directly investigating the association between corticos-
teroid therapy and the risk of thrombosis, treatment with glucocorti-
coids is listed as a potential predisposing cause in most studies of dogs
experiencing thrombosis (LOE 5, Good).19,20,22,23,78 The study with the
highest LOE did not directly address the question, but prospectively
evaluated hemostatic changes in dogs experiencing thrombosis com-
pared to 56 healthy controls and identified 1 dog out of the 7 that was
receiving prednisolone at the time of diagnosis (LOE 2, Fair).79 The only
other prospective study investigated the use of a specific assay to dif-
ferentiate dogs with thrombosis from normal dogs and reported that 2
out of 10 dogs were receiving glucocorticoids (LOE 2, Fair).80
The time frame of glucocorticoid use is not consistent among
studies, ranging from the time of presentation to within a month of
experiencing thrombosis. In the largest retrospective study of dogs
experiencing thrombosis, 34 out of 80 dogs (43%) received treat-
ment with steroids prior to the development of splenic vein throm-
bosis. Of these, 15 dogs also had neoplasia, 12 had immune-mediated
disease, and 8 had pancreatitis.22 Treatment with glucocorticoids
also featured prominently in 2 studies of portal vein thrombosis,
with 10 out 11 dogs in the Van Winkle study and 14 of 33 dogs
in the Respess study receiving glucocorticoids for underlying condi-
tions that also impact hemostasis (immune-mediated disease, neopla-
sia, and pancreatitis).19,20 One retrospective study comparing TEG to
histopathologic evidence of thrombosis in dogs also noted systemic
glucocorticoid therapy in a significant number of enrolled cases (13 of
DELAFORCADE ET AL.
39 dogs); however, this was the only study that attempted correlate
corticosteroid use and necropsy evidence of thrombosis, and no sta-
tistically significant association was found (LOE 5, Fair).81
It is not possible to determine the exact role of corticosteroids on
the development of thrombosis. However, glucocorticoid use is associ-
ated with thrombosis especially in conjunction with other prothrom-
botic disease states. The portal system seems particularly prone to
glucocorticoid-related thrombosis. When choosing to administer corti-
costeroids, their effect on the hemostatic system should be considered
particularly when other prothrombotic states are present.
Cats
Studies investigating hemostatic changes secondary to glucocorticoids
are lacking in cats. Three studies were found that characterized throm-
botic states other than cardiac related ATE in cats. In 1 study of 6 cats
with portal vein thrombosis and in another study of 29 cats with PTE,
glucocorticoid therapy at the time of diagnosis was noted in 2 and 8
cats, respectively (LOE 5, Good).17,21 Glucocorticoid use was not iden-
tified in the third study of 17 cats experiencing thromboembolism.18
Knowledge gaps
Few studies have the primary purpose of investigating the influence of
corticosteroids on development of thrombosis in sick dogs. Although
glucocorticoids use has consistently been identified in dogs with
thrombosis, the time frame of corticosteroid use varies sufficiently
to prevent a strong and direct association with development of
thrombosis.
PECO QUESTION: Hyperadrenocorticism
In dogs (P), is the development of hyperadrenocorticism (HAC) (E) as
opposed to remaining disease free (C) associated with the develop-
ment of thrombosis (O)?
Guidelines
1.5 Hyperadrenocorticism
a. Hyperadrenocorticism (HAC) is associated with thrombosis in
a small subset of dogs only.
b. We suggest HAC should be investigated in dogs presented
with thrombosis.
c. A diagnosis of HAC alone does not warrant antithrombotic
therapy unless other risk factors and/or comorbidities exist.
Evidence summary
Out of 22 papers reviewed, 10 papers (2 LOE 4, 8 LOE 5)
suggest that HAC is associated with the development of
thrombosis.5,15,16,19,22,55,64,82–84 However, all are retrospective
studies or case series and most do not have a control group, with the
exception of 2 studies. Johnson et al reported that 6.9% (2/29) of dogs
with necropsy-confirmed PTE had HAC, which represented 2.7% of all
41
dogs with HAC (n = 91) necropsied during the study period.16 Winter
et al included a control group to evaluate the odds of a dog having
aortic thrombosis according to its sex, age, body weight, and breed,
but not according to underlying condition such as HAC.5 Considering
the 7 retrospective studies with >10 dogs (16–291 dogs/study for
a total of 532 dogs), HAC is reported in 4–17% of dogs diagnosed
with some form of thrombotic event, with an overall mean of 6.2%
(33/532).5,15,16,19,22,24,55 Because of the retrospective nature of
these studies, the role of comorbidities in the generation of throm-
bosis in dogs with hypercortisolemia is difficult to ascertain. Aortic
thrombosis5,24,82,84 and PTE15,16,83 seem most commonly reported in
dogs with hypercortisolemia, but thrombosis in the portal vein,19,20
caudal vena cava,84 and splenic vein,22 as well as splenic infarction55
have also been documented.
Without making a direct association with the development of
thrombosis, 3 additional studies (LOE 2, Fair) have documented a
hypercoagulable state in dogs with HAC.85–87 However, the shift in the
balance of the hemostatic system in dogs with HAC is not a consistent
finding as 2 additional studies (LOE 2, Good; LOE 5, Fair) were not able
to document a hypercoagulable state in dogs with HAC.88,89
Knowledge gaps
The role of comorbidities in the association between HAC and throm-
bosis is not known, but carefully designed epidemiologic studies could
clarify the degree of association between HAC and thrombosis. A
hypercoagulable state is not consistently reported across studies and
additional investigation of the coagulation disturbances in patients
with hypercortisolemia is warranted.
PECO QUESTION: Cancer
In dogs (P), is the development of cancer (E) as opposed to remaining
disease free (C) associated with the development of thrombosis (O)?
Guidelines
1.6 Cancer (dogs only)
a. Cancer in dogs, in particular (adeno)carcinomas, is associated
with the development of thrombosis in a small subset of dogs
only.
b. There is insufficient evidence to support routine anticoagula-
tion of dogs with cancer.
c. We suggest that antithrombotic therapy be considered for
dogs with cancer where hypercoagulability is demonstrated, or
where other risk factors for thrombosis exist.
Evidence summary
Neoplasia is one of the most common underlying disease processes
identified in retrospective studies of canine thrombosis (LOE 5, Poor-
Good).15,19,22,24,63,81 In a large retrospective study of dogs with splenic
42
vein thrombosis, neoplasia was the most common underlying disease
identified, affecting over half of the 80 dogs enrolled (54%).22 In that
study, round cell neoplasia was most common, affecting 20/80 dogs
(25%), whereas in other populations, carcinoma is most commonly
identified. Recent or concurrent glucocorticoid administration compli-
cates the direct assessment of risk in this patient population, affect-
ing 9 of 20 dogs with splenic vein thrombosis in 1 study.22 Thrombosis
was documented in 6/52 dogs (11.5%) with adrenal gland tumors,90 in
4 of 41 dogs that died in a large retrospective study of dogs undergo-
ing splenectomy for splenic masses.11 In a prospective study evaluating
the use of CT scanning to identify PTE, 3/6 dogs with PTE had underly-
ing neoplasia.4
Viscoelastic testing has been used to characterize the hemostatic
dysfunction in dogs with neoplasia. Two prospective studies used
viscoelastic testing in addition to plasma-based assays to charac-
terize hemostatic changes in dogs with neoplasia. The first study
of 71 dogs with malignant neoplasia identified hypercoagulability
in 47/71 dogs (66%), with nonmammary gland carcinomas being
associated with increased clot strength and fibrinogen compared to
other forms of cancer (LOE 3, Poor).91 The second study documented
hypercoagulable changes using TEG in 18/36 (50%) of dogs with
malignant neoplasia, and in 4/13 (31%) dogs with benign neoplasia.
Carcinomas were most commonly diagnosed in dogs with hypercoag-
ulable changes, followed by sarcomas and lymphoma (LOE 3, Poor).92
Interestingly, significantly prolonged aPTT accompanied indicators
of hypercoagulability in both studies. Hypercoagulable changes were
also observed using TEG in a prospective controlled study of 27
dogs with lymphoma (22/27 dogs, 81%; LOE 2),93 and in 15/32 dogs
with carcinoma (46%; LOE 2, Poor).94 In the lymphoma study, serial
evaluation indicated that hypercoagulability persisted throughout
treatment.
Several studies using immunohistochemical staining identified tis-
sue factor and fibrin/fibrinogen deposits in all 24 canine glioma biop-
sies, and increased D-dimers in 17/24 cases (LOE 5, Good).95 In a sim-
ilar study of dogs with meningioma, TF expression was documented
in 26/29 biopsy samples and both D-dimers and fibrinogen/fibrin
were found in all samples.96 Interestingly, microvascular intravascular
thrombosis was documented in both of these studies (15/24 dogs with
gliomas and in 19/29 specimens from dogs with meningiomas). Similar
methodology identified fibrin deposits and thrombus formation in dogs
with mammary gland neoplasia.97
The mechanism of hypercoagulability in dogs with neoplasia
has been investigated and includes overexpression of circulating
tissue factor,92,98 thrombocytosis,94 platelet hyper-reactivity,99
hyperfibrinogenemia,94 and reduced antithrombin activity.66 Three
dogs with neoplasia were included in a prospective controlled study
of 20 dogs investigating endogenous fibrinolytic potential in dogs
with diseases predisposing to thrombosis where resistance to tissue
plasminogen activator induced fibrinolysis was documented in this
group compared to healthy controls (LOE 2, Poor).65
Case reports highlight novel diagnostic or therapeutic approaches
to dogs with neoplasia-associated thrombosis (LOE 5, Fair).100–103
All 4 involved carcinomas and included mammary gland carcinoma
(ATE), islet cell carcinoma (tumor thrombus), adrenocortical carcinoma
DELAFORCADE ET AL.
(external iliac venous thrombosis), and renal tubular cell carcinoma
(caudal vena cava thrombosis).
Knowledge gaps
Despite an association between neoplasia and thrombosis, partic-
ular risk factors for thrombosis formation are not clear, and are
complicated by comorbidities and concurrent therapies. Additional
epidemiologic studies evaluating the incidence of thrombosis in small
animal cancer patients are needed and further delineation of risk
factors would aid identification of patients that might benefit from
thromboprophylaxis.
PECO QUESTION: Sepsis
In dogs (P), is the development of sepsis (E) as opposed to remaining
disease free (C) associated with the development of thrombosis (O)?
Guidelines
1.7 Sepsis (dogs only)
a. Sepsis is associated with the development of thrombosis in a
small subset of dogs only.
b. There is insufficient evidence to support routine anticoagula-
tion of dogs with sepsis.
c. We suggest that antithrombotic therapy be considered for
dogs with sepsis where hypercoagulability is demonstrated, or
where other risk factors for thrombosis exist.
Evidence summary
Sepsis is consistently listed as an underlying cause of thrombosis in ret-
rospective studies of thrombotic conditions in dogs, but most studies
lack controls (LOE 5, Good).15,19,23,24,55,63 Bacterial endocarditis, sep-
tic peritonitis, and aspiration pneumonia are commonly identified24,82 ;
however, the direct association between sepsis and thrombosis is com-
plicated by the frequent presence of concurrent disease processes that
also potentially affect hemostasis including immune-mediated disease
and neoplasia.4 Despite this, hemostatic alterations consistent with
hypercoagulability have been identified in dogs similar to those seen
in people including reduced endogenous anticoagulants (protein C104
and antithrombin66,104 ) increased fibrinogen, increased thrombin acti-
vatable fibrinolysis inhibitor,105 thrombomodulin downregulation,65
and platelet hyperreactivity.106,107
A prospective case-control study of 23 dogs with fungal sepsis (blas-
tomycosis) documented hyperfibrinogenemia, increased thrombin–
antithrombin complex concentration, and hypercoagulable changes
on thromboelastometry compared to 23 case-matched controls,
supporting a hypercoagulable state in this patient population (LOE 2,
Poor).108 Isolated case reports (LOE 5, Fair) describe a dog with endo-
carditis experiencing thrombosis,109 and thrombosis associated with
DELAFORCADE ET AL.
bartonella infection.110 Reports of hemostatic alterations or thrombo-
sis in dogs with infections in the absence of sepsis are lacking, however.
Knowledge gaps
Despite physiologic changes supporting a hypercoagulable state in
dogs with sepsis and evidence of thrombosis in some affected dogs, it
remains unclear which septic patients are at risk for thrombosis. The
contribution of clinically silent thrombosis or microvascular thrombo-
sis to morbidity and mortality associated with sepsis is suspected,111
but is unknown.
PECO QUESTION: Cerebrovascular disease
In dogs (P), is the development of cerebrovascular disease (E) as
opposed to remaining disease free (C) associated with the develop-
ment of thrombosis (O)?
Guidelines
1.8 Cerebrovascular disease
a. Cerebrovascular disease is more likely to result from a throm-
botic event rather than be the cause of one.
b. We suggest that antithrombotic therapy be considered when
an ischemic stroke is identified and a concurrent medical con-
dition associated with a risk for thrombosis is present.
Evidence summary
Cerebrovascular disease defines a brain abnormality caused by a
pathologic interruption of its blood supply. The clinical manifestation of
cerebrovascular disease is termed stroke or cerebrovascular accident,
and can be ischemic or hemorrhagic in origin. Ischemic strokes occur
secondary to a local vascular obstruction (a thrombus), or a vascular
obstruction originating from a distant site (thromboembolism).112 In a
retrospective study of 33 dogs with brain infarction, a concurrent dis-
ease was identified in 18 dogs, with chronic kidney disease (8/33) and
HAC (6/33) being most commonly identified. No concurrent disease
was noted in 15 dogs. Five of the 10 dogs that underwent postmortem
examination had evidence of cerebrovascular thrombosis. Of these
dogs, 2 had no underlying disease identified, while the 3 others had
PLN, HAC, or hemangiosarcoma identified (LOE 5, Fair).113 In another
study of 8 dogs with brain infarction identified via CT, 6 of 8 dogs had
concurrent diseases including hypothyroidism, chronic renal disease,
pyometra, and HAC (LOE 5, Fair).114 A third study of 22 dogs included
4 dogs with concurrent medical diseases that could have predisposed
to ischemic stroke. These included cardiovascular disease, HAC, and
neoplasia (LOE 5, Fair).115 These studies suggest that ischemic strokes
are the result of the hypercoagulable conditions rather than a risk fac-
tor for thrombosis themselves. None of the dogs included in retro-
spective studies of PTE, ATE, portal vein, or splenic vein thrombosis
had cerebrovascular disease.5,15,16,19,20,22,24,55,82,83 For these reasons,
43
there is insufficient evidence to support a direct association between
cerebrovascular disease and thrombosis.
Knowledge gaps
There is insufficient evidence to support an association between
cerebrovascular disease and thrombosis. Additional investigations
of patients with documented cerebrovascular disease for potential
thrombosis and thrombotic risk factors are warranted.
PECO QUESTION: Cardiac disease in cats
In cats (P), is the development of cardiac disease (E) as opposed
to remaining disease free (C) associated with the development of
thrombosis (O)?
Guidelines
1.9 Cardiac disease (cats only)
a. Feline cardiomyopathy (hypertrophic cardiomyopathy [HCM],
restrictive cardiomyopathy [RCM], unclassified cardiomyopa-
thy [UCM], and dilated cardiomyopathy [DCM] is strongly
associated with risk of ATE.
b. Cats with a history of ATE, left atrial (LA) dilation, spontaneous
echocontrast, or reduced LA appendage flow velocity may be
at particular risk.
c. We recommend antithrombotic therapy for cats with car-
diomyopathy, particularly in those with the above risk factors.
Evidence summary
Three studies strongly support the association of feline cardiac dis-
eases with arterial thromboembolic phenomena. In particular, the link
is strongest for HCM and ATE, but it is likely that other feline car-
diomyopathies and other cardiac diseases such as inherited valvular
malformations increase the risk of ATE. The best evidence comes with
a recent study quantifying the cumulative risk of ATE in 1,730 cats
over 10 years. In this study, the cumulative risk of ATE at 1, 5, and
10 years was 3.5%, 9.5%, and 11.3%, respectively, in cats with HCM
or hypertrophic obstructive cardiomyopathy compared to 0.0%, 0.4%,
and 0.7%, respectively, in apparently healthy cats (LOE 2, Good).116
Another study of 309 cats with renal infarcts found that these cats
were 8 times more likely to experience distal ATE compared to time
matched controls, and as well as a positive association between renal
infarcts, HCM and ATE. These findings support feline HCM as a risk
factor for thrombosis (LOE 4, Good).117 In a third prospective case-
controlled study, cats with spontaneous echocontrast or atrial thrombi
met the laboratory criteria for hypercoagulability, further supporting a
hypercoagulable state in cats with cardiac disease (LOE 2, Good).118
Several studies were overall classified as neutral to the PECO
question (1 LOE 2, Good; 3 LOE 4, Fair; 1 LOE 4, Good) but do provide
potential intermediary links between feline cardiac disease and ATE.
44
Specifically, these studies suggest that feline cardiac disease accompa-
nied by spontaneous echocontrast, LA dilation, reduced LA function,
and low flow velocities may portend ATE or death.25,119–122
Numerous additional studies were considered neutral to the PECO
question, primarily because they lack a control population; however,
the collective weight of these studies strongly suggests that feline car-
diac disease and ATE are linked. There was very limited evidence that
feline cardiac disease is a risk factor for venous thrombosis, however.
No studies were identified that suggested evidence contrary to the
presence of an association between cardiac disease and thromboem-
bolism in cats.
Knowledge gaps
The veterinary literature suggests a high risk of ATE in cats with car-
diomyopathy, although there is much less evidence to support or refute
an association between ATE and other types of feline cardiac disease.
The degree of association between feline cardiac disease and venous
thromboembolism (VTE) is unknown.
PECO QUESTION: Cardiac disease in dogs
In dogs (P), is the development of cardiac disease (E) as opposed to
remaining disease free (C) associated with the development of throm-
bosis (O)?
Guidelines
1.10 Cardiac disease (dogs only)
a. Canine cardiac diseases are not associated with a high risk of
development of thrombosis.
b. We suggest that antithrombotic therapy be considered in
individual dogs where other risk factors for thrombosis exist.
Evidence summary
There is very limited evidence linking cardiac disease in dogs to the
development of venous or arterial thrombosis. Only 1 study was iden-
tified linking cardiac disease in dogs to the development of thrombosis
(LOE 4, Fair).78 Most studies were poorly designed, small, and offered
limited evidence in either direction and hence were considered neutral
to the PECO question.15,23,71,82,123–125 There was a similar LOE refut-
ing a link between thrombosis and cardiac disease in dogs as suggesting
it.5,14,55 There were numerous case series and several case reports in
individual dogs, but in the context of the substantial numbers of dogs
with cardiac disease worldwide, the number of reports of thrombosis
was very small comparatively.
Overall ATE appears to be very uncommon in dogs and is most
frequently associated with PLN, neoplasia, and HAC. Cardiac disease
has been identified in some dogs with ATE, but is absent in other com-
parable populations. As such, the degree of association is very weak.
Some evidence suggests that dogs with congestive heart failure (CHF)
may have a hypercoagulable state, but it is not clear if or how this
DELAFORCADE ET AL.
translates into a thrombotic risk. Cavalier King Charles Spaniels may
be predisposed to vascular anomalies or vascular injuries that might
be prothrombotic, but a clear link to cardiac disease in these dogs
has not been demonstrated. As such, there is not sufficient evidence
to suggest that dogs with cardiomyopathy or with valvular disease
warrant thromboprophylaxis. It would be reasonable for clinicians to
consider thromboprophylaxis in individual dogs with cardiac disease
that demonstrate particular propensity for clot formation, appear
hypercoagulable based on coagulation profiling, or have concurrent
risk factors.
Knowledge gaps
While some dogs with CHF may have a hypercoagulable state, the
degree to which this translates to a risk of thrombosis is not clear.
Additional guidelines
These 2 additional sets of guidelines were not constructed in response
to a single PECO question, but represent an attempt to integrate all
of the available information discussed above to provide overall assess-
ments of thrombotic risk. The panel recognized that guidelines on over-
all risk stratification might aid clinical practice and were necessary for
structuring the advice on periprocedural withdrawal and discontinu-
ation of antithrombotics (see also Domain 5). These additional guide-
lines were subjected to the Delphi survey process and represent the
consensus of the panel.
1.11 We define high risk for thrombosis as
a. Dogs with IMHA or PLN.
b. Cats with cardiomyopathy and associated risk factors (see (1)
of Section 10.1).
c. Dogs or cats with >1 disease/risk factor for thrombosis (eg,
pancreatitis with sepsis).
1.12 We define low/moderate risk for thrombosis as
a. Dogs or cats with a single risk factor/disease.
b. Dogs or cats with known risk factor conditions that, with
treatment, are likely to resolve in days to weeks.
Evidence summary
When considering initiation of antithrombotic therapy, an assessment
of individual risk for thrombosis or thromboembolism is necessary.
Individual risk should account for the underlying condition, the inflam-
matory state of the animal, and the likelihood the underlying condition
can be resolved. Specific diseases, as documented above, are strongly
associated with an increased risk for thrombosis (including IMHA and
PLN in dogs, and cardiomyopathy in the cat). The risk for thrombosis
associated with other diseases is less clear, and reference to human
guidelines provides a rational approach until further prospective stud-
ies can be completed. A reasonable assessment of risk must balance
the perceived danger of thrombosis, with the possible harm (ie, hem-
orrhage) that may result from specific antithrombotic therapies. In
DELAFORCADE ET AL.
human medical patients, the Padua prediction score considers risk fac-
tors such as active neoplasia, prior VTE, conditions known to cause a
hypercoagulable state, reduced mobility, recent trauma, elderly age,
acute myocardial infarction or ischemic stroke, heart or respiratory
failure, acute infection or rheumatologic disorder, obesity, and ongoing
hormonal therapy.123 Each of the first 4 categories is worth 3 points,
recent trauma or surgery is worth 2 points, and the remainders are
worth 1 point. Patients with scores above 4 are considered to be at
high risk for VTE. Recent models have also integrated the concentra-
tion of circulating D-dimer into risk scoring.124 Both patient and pro-
cedure specific risks for postoperative thromboembolism have been
documented in human patients undergoing nonorthopedic surgery,125
but these data have not been compiled for veterinary patients. Some
retrospective reports of adrenalectomy in dogs (LOE 2, Poor) have
reported postoperative thrombosis, particularly in dogs that already
had evidence of tumor invasion into the vena cava,90,126 but this has
not been documented in other studies with similar populations.127 In
addition, the procoagulant influence of inflammation in diseases asso-
ciated with systemic illness (eg, sepsis, pancreatitis, and severe trauma)
and the presence of other factors (eg, central venous catheters)23 may
also help to characterize levels of risk in veterinary patients, although
this is difficult to quantify given the available evidence.
CONFLICT OF INTEREST
The authors declare no conflicts of interest.
ORCID
Lenore Bacek DVM, MS, DACVECC
https://orcid.org/0000-0002-1046-9297
Marie-Claude Blais DVM, DACVIM
https://orcid.org/0000-0003-0877-4425
Robert Goggs BVSc, DACVECC, DECVECC, PhD
https://orcid.org/0000-0001-7446-6987
Alex Lynch BVSc (Hons), DACVECC
https://orcid.org/0000-0002-8747-094X
Elizabeth Rozanski DVM, DACVIM, DACVECC
https://orcid.org/0000-0003-3233-8930
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How to cite this article: deLaforcade A, Bacek L, Blais
M-C, Goggs R, Lynch A, Rozanski E. Consensus on the
Rational Use of Antithrombotics in Veterinary Critical Care
(CURATIVE): Domain 1—Defining populations at risk. Jour-
nal of Veterinary Emergency and Critical Care. 2019;29:37–48.
https://doi.org/10.1111/vec.12797