Article #3
CE
Canine Rocky Mountain Spotted Fever
Rochelle M. Low, DVM
Jennifer L. Holm, DVM, DACVECC
Angell Animal Medical Center
Boston, Massachusetts
ABSTRACT:
Rocky Mountain spotted fever (RMSF) is an acute, infectious tick-borne disease in dogs.
The causative agent of RMSF is Rickettsia rickettsii, a gram-negative bacterium transmitted
by ixodid ticks. The most common clinical signs are often nonspecific and include
lethargy, anorexia, and fever. Because the primary targets of R. rickettsii are endothelial
cells of blood vessels, any organ can be affected, possibly resulting in multiorgan dysfunction. Prompt treatment early in the course of infection may reduce morbidity and mortality associated with RMSF. This article discusses the epidemiology, pathophysiology,
diagnosis, and treatment of RMSF in dogs.
R
ickettsia rickettsii is a gram-negative, obligate intracellular coccobacillus transmitted
by hard-bodied ticks that can infect vertebrates, including humans and dogs. Rocky Mountain spotted fever (RMSF) is currently the most
common and potentially devastating rickettsial illness in both humans and dogs in the United
States. Delayed diagnosis and initiation of treatment have led to a case fatality rate of 2% to 5% in
humans.1 The case fatality rate in dogs has not
been established, although a recent retrospective
study 2 documented a 100% survival rate. However, mortality in one veterinary study was three of
five (60%), presumably because of delayed diagnosis and more severe manifestations of disease.3
Greater understanding of the pathophysiology and
diagnosis of this disease may enable earlier initiation of therapy and improve prognosis in dogs.
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COMPENDIUM
EPIDEMIOLOGY
At least 23 rickettsial species
have been described. The
Rickettsia genus is divided into
four groups: typhus, spotted
fever, ehrlichiosis, and bar-
530
tonella.4 Rickettsiae survive in nature by replication in cells of small mammals and arthropods.
Rickettsial diseases are important causes of morbidity and mortality worldwide, with an estimated 900 humans afflicted annually in the
United States.5 Although RMSF is classified as
a reportable disease in humans, the true incidence is believed to be underestimated.6
The primary route of R. rickettsii transmission is tick bites. Transmission requires 5 to 20
hours of tick attachment, making prompt tick
removal a priority in preventing RMSF.5 The
main tick vector for RMSF in the eastern
United States is Dermacentor variabilis, whereas
Dermacentor andersonii is the main vector in the
western United States and Canada.7,8 Humans
and dogs can also become infected through
ingestion of an infected tick or direct contamination of a wound by tick feces or secretions
from the tick coxial gland. There are no reports
of direct transmission between humans and
dogs. However, there have been cases of RMSF
in humans and dogs living in the same household or geographic area that have been caused
by concurrent exposure to infected ticks.9,10
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Canine Rocky Mountain Spotted Fever CE
RMSF occurs in humans and dogs in the United
States, Canada, and Central and South America.11,12 The
average incubation period of R. rickettsii in both humans
and dogs is 1 week, with a reported range of 2 to 14
531
bines with protein S to inactivate factors Va and VIIIa as
well as plasminogen activator inhibitor-1 (PAI-1).19
Rickettsial organisms enter endothelial cells through
induced phagocytosis. After rickettsial infection, the
RMSF in dogs can cause severe vasculitis and a wide range
of clinical manifestations, including fever, ocular lesions,
neurologic dysfunction, arthropathy, and edema.
days. Most cases occur from April through October,
coinciding with peak tick activity.11 In the continental
United States, RMSF has been diagnosed in every state
except Vermont and Alaska. The incidence of RMSF is
actually lower in the Rocky Mountains than in other
parts of the country. The highest infection rates in dogs
are now in the southeastern United States.2,11
PATHOPHYSIOLOGY
R. rickettsii infects vascular endothelial cells, initiating
diffuse vasculopathy, a severe perivascular inflammatory
response, and microvascular thrombosis.13,14 The pathogenesis of R. rickettsii infection is not completely understood;
however, a combination of three mechanisms is described
in the recent literature. First, the endothelial cell response
to injury leads to promotion of a proinflammatory and
prothrombotic state. Second, microvascular
thrombosis and endothelial injury cause
oxidative stress that leads to cell death. Finally,
platelet homeostasis is further affected by
immune-mediated platelet destruction.15–17
Endothelial Response to Injury
The vascular endothelium is critical in protecting against vascular injury, maintaining
blood fluidity, and preventing thrombosis.18
Thrombosis is prevented by production of
antiplatelet, anticoagulant, and fibrinolytic
factors. The role of the endothelium in preventing thrombosis has recently been
reviewed.19 Normal endothelial anticoagulant
and fibrinolytic properties are achieved by
production of thrombomodulin, protein S,
heparin sulfate, tissue factor pathway
inhibitor, and tissue plasminogen activator.
Thrombomodulin binds to thrombin, and
this complex activates protein C, which comJuly 2005
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surface of the endothelial cell undergoes biochemical
changes induced by three possible mechanisms20:
•
•
•
Enzymatic effects secondary to rickettsial entry
Altered synthesis and expression of cell surface
components
Expression of rickettsial antigens on the cell surface
after infection
Studies using human cultured endothelial cells have
shown that the host endothelial cell not only sustains
damage but also actively responds to intracellular damage.21 This active response to infection by endothelial
cells involves altering the expression of several proteins
that play an important role in the biochemical and
pathologic changes in RMSF.13 In addition, endothelial
532
CE Canine Rocky Mountain Spotted Fever
PAI-1
Tissue factor
A
to
pop
ntia
O2
tic
NF-κB
O2•
GSH
2H2O
SOD
H2O2
H2O + O2
R. rickettsii
Platelets
Neutrophil
–
OH• + OH
Normal cell
Infected cell
Endothelial cell
Figure 1. Endothelial cells respond to R. rickettsii
infection with increased production of inflammatory and
procoagulant proteins, increased platelet and neutrophil
adhesion, and expression of antiapoptotic proteins.
injury has been shown to exacerbate the inflammatory
response with neutrophil activation, increased neutrophil–endothelial adhesion, and increased release of
proinflammatory cytokines.11,13,21
Specific endothelial cell changes in RMSF include
increased surface adhesiveness to platelets and changes
in endothelial cell gene expression, leading to increased
production of key proinflammatory and procoagulant
proteins, such as PAI-1 and tissue factor21 (Figure 1).
PAI-1 quickly inhibits conversion of plasminogen to
plasmin and thus is a powerful procoagulant protein.22,23
Another protein released by endothelial cells during R.
rickettsii infection is the transcription factor nuclear
factor–κB (NF-κB). NF-κB activation has a critical role
in protecting cells from apoptosis. It has recently been
demonstrated that R. rickettsii exerts an antiapoptotic
effect on host cells by increasing NF-κB production,
thereby protecting itself by ensuring survival of the host
cell. This antiapoptotic effect favors a higher tick rickettsemia. In addition to its antiapoptotic effect, NF-κB
activation in RMSF plays a critical role in promoting a
prothrombotic state by inducing expression of the procoagulant protein tissue factor.24
Oxidative Injury
During normal cellular respiration, oxygen is reduced
to water. The metabolism of one molecule of oxygen
requires four chemical reduction reactions that lead to
production of reactive oxygen species (Figure 2). The
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α-Lipoic acid
Normal cell
2H2O
Figure 2. Two important intracellular enzymes
contribute to antioxidant defense: Glutathione peroxidase
(GSH) converts peroxide to water, and superoxide
dismutase catalase (SOD) converts peroxide to water and
oxygen. (• = free radicals)
body normally keeps these free radicals under control by
producing antioxidants. However, if production of free
radicals exceeds the antioxidant defense mechanism, a
condition known as oxidative stress occurs. Oxidative
stress leading to lipid peroxidation of cell membranes has
been implicated as an important mechanism of cellular
injury in numerous diseases, including RMSF.15,17,25
Interaction of R. rickettsii with endothelial tissue leads
to generation of reactive oxygen species. Intracellular multiplication of R. rickettsii changes the internal morphology
of endothelial cells. Architectural changes in the cytoskeleton of infected cells, such as dilation of membranes of
the endoplasmic reticulum and outer nuclear membrane,
directly affect the host-cell antioxidant defense system.26
The three enzymatic antioxidants important in normal
cellular defense against reactive oxygen species are catalase, glutathione peroxidase, and glucose-6-phosphate
dehydrogenase. Activity of these three enzymes is significantly reduced in endothelial cells infected with R. rickettsii.25 Decreased levels of these enzymes make infected
endothelial cells vulnerable to oxidative stress. Damage
associated with oxidative injury in RMSF is supported by
the fact that humans with glucose-6-phosphate dehydrogenase deficiency have a more severe course of infection.27
In addition, experimental studies using cultured human
endothelial cells have shown that the level of peroxides (a
reactive oxygen species) increases in endothelial cells
infected by R. rickettsii.28,29
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CE Canine Rocky Mountain Spotted Fever
Figure 3. Anterior uveitis with hyphema in a dog that
Figure 4. Hyphema and iris hemorrhage in a dog with
tested positive for RMSF. (Courtesy of Dr.William Greentree,
Angell Animal Medical Center, Boston, MA)
RMSF. (Courtesy of Dr. William Greentree, Angell Animal
Medical Center, Boston, MA)
Clinical use of exogenous antioxidants and the ability
to inhibit down-regulation of endogenous antioxidant
enzymes may be critical in ensuring survival of the host
cell and ultimately improving the outcome of the disease.26 One study15 recently focused on the antioxidant
α-lipoic acid, which is an important constituent of cell
membranes. α-Lipoic acid is easily absorbed from the
diet and has been proposed as an adjunctive therapy for
RMSF. α-Lipoic acid has the capacity to directly bind
reactive oxygen species and decrease NF-κB activation.15
role, the presence of elevated platelet-associated IgG
titers in sera of infected dogs suggests that antibody
coating of platelets is occurring.30 Detection of patients
with an immune-mediated component causing platelet
destruction in RMSF is important because additional
immunosuppressive therapy may be required, especially
in the early stages.
Immune-Mediated Platelet Destruction
Thrombocytopenia is the most consistent (reported in
up to 80% of dogs) laboratory finding in canine rickettsial
disease.2,30 The mechanism of this rickettsial-induced
thrombocytopenia varies with rickettsial species. Historically, thrombocytopenia induced by RMSF has mainly
been attributed to increased platelet use secondary to vasculitis.2,30 Essentially, damage to the vascular endothelium
exposes subendothelial collagen, leading to increased
platelet adhesion and aggregation as well as decreased
systemic circulation of platelets. Recently, elevated
platelet-associated IgG titers were demonstrated in dogs
with both experimentally induced and naturally occurring
RMSF, suggesting the possibility of immune-mediated
platelet destruction in addition to increased use.30
Although an immune component to thrombocytopenia associated with RMSF likely plays only a secondary
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DIAGNOSIS
Preliminary diagnosis of RMSF is based on clinical
and laboratory findings. Because the clinical and laboratory changes are often vague and nonspecific, a broad
differential diagnosis must be considered. Important
diagnostic differentials include other tick-borne diseases, immune-mediated thrombocytopenia, systemic
lupus erythematosus, sepsis, and neoplasia.5
Clinical Signs
In a recent retrospective report 2 of 30 dogs with
RMSF, the most common clinical signs were lethargy,
anorexia, fever, ocular abnormalities, weight loss, lymphadenomegaly, and edema. Less common clinical signs
included arthropathy, cutaneous necrosis, petechiae/
ecchymoses, and myalgia. Dogs with IgM antibody
titers of 1:1024 or greater at presentation were more
likely to have neurologic dysfunction and skin lesions.2
Ocular manifestations in RMSF occur secondary to
vasculitis and are considered useful in the diagnostic
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Canine Rocky Mountain Spotted Fever CE
535
evaluation. Davidson et al31 reported that nine of 11
consecutive dogs with RMSF had ocular involvement.
Ocular findings were bilateral in eight of nine dogs and
included conjunctival vascular injection (nine dogs),
multifocal retinal hemorrhages (seven dogs), anterior
uveitis (six dogs; Figure 3), petechial hemorrhages in the
iris stroma (two dogs; Figure 4), and bilateral hyphema
(one dog). Ocular hemorrhages are the most common
ophthalmic sign of RMSF.32 With appropriate treatment, most ocular signs resolved within 2 to 5 days.31
Although the most common cutaneous lesions in
RMSF are edema (Figure 5) as well as petechial and
ecchymotic hemorrhages, severe dermal necrosis has been
reported in four dogs with RMSF. Dermal necrosis occurred in regions in which edema and hemorrhage were
most severe, such as the scrotum, pinnae, and limbs.33
Laboratory Findings
Laboratory findings in patients with RMSF vary and
are nonspecific. Thrombocyte numbers typically drop
rapidly but may be normal early in the course of disease.11
In a retrospective study of 30 canine RMSF cases, Gasser
et al2 found that 26 of 30 (85%) dogs were thrombocytopenic at initial presentation. Other laboratory abnormalities include increased liver enzymes, azotemia,
coagulation abnormalities, leukocytosis, anemia, hypoal-
Figure 5. Vasculitis causing severe peripheral edema in
a dog with RMSF.
RMSF.11,32 Diagnosis can also be demonstrated by a
fourfold or greater rise in IgG titer between the acuteand convalescent-phase specimens. These two samples
are normally taken 3 to 4 weeks apart.34–36 A positive
polymerase chain reaction test for R. rickettsii or a posi-
Initial diagnosis of RMSF is based on clinical and laboratory
findings and is confirmed with a fourfold rise in acute
to convalescent titer to R. rickettsii or a single IgM titer
greater than 1:64 at least 7 days after the onset of clinical signs.
buminemia, hypercholesterolemia, hyponatremia, and
lymphocytic pleocytosis in cerebrospinal fluid.3
Immunofluorescent antibody (IFA) titer is considered
the gold standard in diagnosing RMSF. This test is useful in confirming the clinical diagnosis because antibodies to R. rickettsii are rarely detected during the first 7
days of illness.32 The IFA titer can detect IgM and IgG
antibodies to R. rickettsii. IgG levels take 2 to 3 weeks to
rise after infection and may not decline for 3 to 5
months, whereas the IgM titer usually increases before
the IgG titer and declines 6 to 8 weeks after infection.
Thus a single IFA titer of 64 or more for IgM, with
appropriate clinical signs, is considered diagnostic of
July 2005
tive immunofluorescence result from a skin biopsy is
also considered diagnostic, but these results are neither
timely nor practical in most clinical settings.36
TREATMENT
The primary therapeutic goals for RMSF include
early, appropriate antibiotic therapy and supportive care,
such as intravenous fluids, to prevent organ dysfunction.
In addition, adjunct treatments such as corticosteroids,
anticoagulants, and antioxidants can be considered.
Early antibiotic administration may prevent development of severe thrombosis and dermal lesions as well as
ultimately improve the outcome.11,16,32
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CE Canine Rocky Mountain Spotted Fever
Antibiotics proven to be effective against experimental R. rickettsii infection in dogs include tetracycline and
its semisynthetic derivative doxycycline, certain fluoroquinolones (i.e., enrofloxacin, trovafloxacin), and chloramphenicol.37–39 In these experimental studies, therapy
for 7 days was shown to be sufficient. Doxycycline is the
drug of choice in dogs because treating ehrlichiosis (i.e.,
another rickettsial infection with similar clinical signs)
with fluoroquinolones has proven ineffective.40 Although doxycycline is considered less likely to cause dis-
promising results in its ability to directly bind reactive
oxygen species and protect cell membranes.15
Preventing tick-borne disease in dogs is extremely
important.11,36 No vaccines are currently available for
administration in dogs. The only effective means of preventing RMSF are avoidance of tick bites and prompt
removal of attached ticks.34 Suggested preventive measures include avoiding tick-infested areas between April
and October, wearing protective clothing, applying
appropriate insect repellants to both humans and pets,
Although RMSF is not directly transmitted from
animals to humans, dogs can harbor the organism
and may increase the chance of human exposure.
coloration of teeth than is tetracycline, some authors
advocate administering chloramphenicol in young animals to avoid this potential problem.38,39
Administering antiinflammatory or immunosuppressive corticosteroid therapy is controversial, especially in
cases with ocular involvement and hematologic abnormalities such as anemia and thrombocytopenia. It is recommended that ocular lesions involving the posterior
segment (i.e., chorioretinitis, retinal hemorrhage/
detachment) should be treated with systemic steroids,
whereas topical steroids should be used to treat anterior
uveitis or hyphema. 31 Because immune-mediated
destruction of platelets is likely a component in thrombocytopenia associated with RMSF and a primary diagnostic differential in many cases, immunosuppressive
therapy may be warranted.32,41 An experimental study41
in dogs showed that concurrent use of prednisone at
antiinflammatory or immunosuppressive doses along
with doxycycline did not worsen the severity of R. rickettsii infection. However, the authors of this study caution against extrapolating these results to dogs with
severe RMSF because the experimentally induced disease was considered mild to moderate in severity.41
Other treatments proposed in humans with RMSF
include use of anticoagulants and antioxidants, but
information is limited. If diffuse evidence of microthrombi is suspected clinically, mini doses of heparin
have been advocated by some authors.42,43 Clinical
administration of antioxidants in patients with RMSF
to limit free radical damage is currently an active area of
study. As mentioned earlier, α-lipoic acid has shown
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checking animals and children daily for attached ticks if
in endemic areas, removing garden refuse, keeping lawns
mowed, avoiding tall grass, and promptly removing
attached ticks.11,37,44 We refer readers to a recent review45
of tick repellants and more detailed information on preventing tick-borne disease.
CONCLUSION
RMSF is the most common rickettsial disease in dogs
in the United States. Damage to the vascular endothelium, oxidative injury, and immune-mediated platelet
destruction are all believed to contribute to the pathophysiology of RMSF. Common clinical signs include
lethargy, anorexia, fever, ocular abnormalities, lymphadenomegaly, and edema. Tentative diagnosis is based
on clinical signs and history, whereas a definitive diagnosis is obtained via IFA titer. A single IgM titer greater
than 1:64 or a fourfold rise in acute to convalescent IgG
titer confirms a diagnosis of RMSF. Treatment recommendations include appropriate antibiotic therapy and
supportive care to prevent multiorgan dysfunction.
Adjunct treatments to consider include anticoagulant,
antioxidant, and/or immunosuppressive therapy. The
prognosis is good if patients are treated early in the
course of the disease.
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Canine Rocky Mountain Spotted Fever CE
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11. Sexton DJ, Kaye KS: Rocky Mountain spotted fever. Med Clin North Am
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14. Kwitkowski VE: Infectious disease emergencies in primary care. Lippincott’s
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15. Eremeeva MA, Silverman DJ: Effects of the antioxidant α-lipoic acid on
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16. Walker DH: Rocky Mountain spotted fever: A seasonal alert. Clin Infect Dis
20:1111–1117, 1995.
17. Silverman DJ, Santucci LA: Potential for free radical–induced lipid peroxidation as a cause of endothelial cell injury in Rocky Mountain spotted fever.
Infect Immunol 56(12):3110–3115, 1988.
18. Bombeli T, Karsan A, Tait JF, et al: Apoptotic vascular endothelial cells
become procoagulant. Blood 89(7):2429–2442, 1997.
19. Good LI, Manning AM: Thromboembolic disease: Physiology of hemostasis
and pathophysiology of thrombosis. Compend Contin Educ Pract Vet 25(9):
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20. Elghetany MT, Walker DH: Hemostatic changes in Rocky Mountain spotted fever and Mediterranean spotted fever. Am J Clin Pathol 112:159–168,
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21. Clifton DR, Goss RA, van Antwerp D, et al: NF-κB–dependent inhibition
of apoptosis is essential for host cell survival during Rickettsia rickettsii infection. Proc Natl Acad Sci 95:4646–4651, 1998.
22. Shi RJ, Simpson-Haidaris PJ, Marder VJ, et al: Increased expression of plasminogen activator inhibitor-1 in R. ricketsii–infected endothelial cells.
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40. Neer TM, Eddlestone SM, Gaunt SD, Corstvet RE: Efficacy of enrofloxacin
for the treatment of experimentally induced Ehrlichia canis infection: J Vet
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41. Breitschwerdt EB, Davidson MG, Hegarty BC, et al: Prednisolone at antiinflammatory or immunosuppressive dosages in conjunction with doxycycline
does not potentiate the severity of R. rickettsii infection in dogs: Antimicrob
Agents Chemother 41(1):141–147, 1997.
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conorii–induced coagulative and platelet activation in vivo in patients with
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1. Normal endothelial cell functions do not include
a. maintenance of vascular tone.
b. transport of nutrients across the endothelium.
c. maintenance of a thromboresistant surface.
d. secretion of von Willebrand factor.
e. secretion of antithrombin.
2. Which statement regarding transcription factor
NF-κB is incorrect?
a. It is critical in protecting endothelial cells from apoptosis in patients with RMSF.
b. It normally resides in the endothelial cell cytoplasm
as an active pool.
c. It induces the expression of tissue factor in patients
infected with R. rickettsii.
d. It is a common response of the host cell to a variety
of infectious agents.
e. none of the above
3. The three enzymatic antioxidants in the body
are
a. catalase, selenium, and glutathione peroxidase.
b. ascorbic acid, selenium, and catalase.
c. glucose-6-phosphate dehydrogenase, catalase, and
selenium.
d. catalase, glutathione peroxidase, and glucose-6-phosphate dehydrogenase.
e. ascorbic acid, selenium, and iron.
4. Which statement regarding R. rickettsii is incorrect?
a. It is an arthropod-associated bacterium.
b. It is a gram-negative obligate intracellular bacterium.
c. Its primary targets are endothelial cells of small vessels and lymphocytes.
d. It cannot be directly transmitted between animals
and humans.
e. none of the above
5. The average incubation of R. rickettsii in humans
and dogs is
a. 14 days.
b. 1 to 3 days.
c. longer than 30 days.
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d. 7 days.
e. 12 hours.
6. Endothelial cell changes in patients with RMSF
do not include
a. increased surface adhesiveness to platelets.
b. production of the procoagulant protein PAI-1.
c. increased production of tissue factor.
d. down-regulation of NF-κB.
e. none of the above
7. A single IFA titer of 64 or more for _____, with
appropriate clinical signs, is diagnostic of RMSF.
a. IgG
b. IgA
c. IgG or IgA
d. IgM
e. IFA titers must be higher than 128 to be clinically
significant.
8. Which antibiotic has not been proven to be
effective in treating RMSF?
a. doxycycline
b. trovafloxacin
c. chloramphenicol
d. enrofloxacin
e. ampicillin
9. Which of the following is ineffective in preventing
tick-borne disease?
a. vaccination
b. prompt removal of attached ticks
c. wearing protective clothing to avoid tick bites
d. avoiding tick-infested areas during peak tick season
e. none of the above
10. Thrombocytopenia associated with RMSF is not
attributed to
a. increased platelet use secondary to vasculitis.
b. immune-mediated platelet destruction.
c. bone marrow suppression.
d. a and b
e. none of the above
Test answers now available at CompendiumVet.com
July 2005