Vol. 22, No.
11 November 2000
CE Refereed Peer Review
FOCAL POINT
★Thrombocytopenia can be a
common sequela of several kinds
of neoplasia; understanding the
pathophysiologic mechanisms of
paraneoplastic thrombocytopenia
is helpful in characterizing and
treating the condition in veterinary
oncologic patients.
KEY FACTS
■ Lymphoproliferative cancers
represent the greatest proportion
of malignancies accompanied by
thrombocytopenia.
■ Thrombocytopenia is documented
in at least 50% of dogs with
hemangiosarcoma.
■ Thrombocytopenia in marrow-
infiltrating tumors can be caused
by myelophthisis or hematopoietic
suppression mediated by changes
in the marrow microenvironment
induced by the presence of
infiltrating malignant cells.
■ Platelet life span is shortened
in dogs with such tumors as
adenocarcinomas, lymphomas,
and sarcomas.
■ At least 50% of dogs with
hemangiosarcoma have
compensated or fulminant
disseminated intravascular
coagulation.
Mechanisms of
Thrombocytopenia
in Dogs with Cancer
Auburn University
Alexandra Chisholm-Chait, VMD
ABSTRACT: The mechanisms of paraneoplastic thrombocytopenia fall into several categories:
decreased production of platelets, platelet destruction, accelerated platelet consumption,
platelet loss through hemorrhage, and sequestration. Dogs with lymphoproliferative neo-
plasms, myeloproliferative/myelodysplastic disorders, and hemangiosarcoma are at increased
risk for developing thrombocytopenia. This article describes the pathogenesis of thrombocy-
topenia in dogs with cancer.
I
n the past few decades, veterinary medicine has experienced an unprecedent-
ed increase in the number of pet owners electing to pursue diagnosis and
treatment of their pets with cancer. In turn, this trend toward more aggres-
sive intervention has provided many opportunities to better characterize the
hematologic disturbances accompanying these malignancies. The incidence of
clinical and subclinical coagulation abnormalities in humans and dogs with can-
cer is surprisingly high (98%1 and 83%,2 respectively). It is difficult to determine
whether these high percentages are a reflection of older data acquired when co-
agulation testing was limited to patients with evidence of a bleeding diathesis.
Despite the paucity of more contemporary veterinary literature in this area,
the few recent studies appear to corroborate earlier human and veterinary data.
For example, an older study documented 10% to 30% of human cancer patients
as having concurrent thrombocytopenia.3 Several studies published from 1980
to 1994 have documented similar incidences of thrombocytopenia in dogs diag-
nosed with neoplasia; all report that low platelet counts are the most common
hemostatic abnormality, with the incidence ranging from 10% to 36%.2,4,5 The
range of these percentages may reflect the specific tumor types represented, with
earlier studies characterizing primarily large, invasive neoplasias.2 Nevertheless,
the studies do concur about which tumor categories represent particularly high
risk factors for the development of thrombocytopenia.
Lymphoproliferative cancers represent the greatest proportion of neoplasms
accompanied by thrombocytopenia; approximately 35% to 50% of dogs with
lymphoproliferative neoplasms are reported to be thrombocytopenic.4,6 Throm-
bocytopenia is also reported to occur more frequently in dogs with carcinomas,
Compendium November 2000 Small Animal/Exotics

hematopoietic tumors, and he- Myelophthisis (i.e., crowd-

mangiosarcoma.4 ing out of normal marrow
Studies investigating the in- constituents by tumor cells) is
cidence of thrombocytopenia characterized by peripheral
within specific tumor cate- pancytopenias. Specific sup-
gories showed that approx- pression of thrombopoiesis
imately 50% of dogs with has been attributed to re-
hemangiosarcoma were throm- duced blood supply caused by
bocytopenic compared with occlusive tumor thrombi
37% of dogs with lymphoma, within the marrow vascula-
25% of dogs with pulmonary ture, competition for nutri-
carcinomas, and 19% of dogs ents between tumor and nor-
with nasal adenocarcinoma.4 Figure 1—Bone marrow cytology showing marrow infil- mal myeloid cells, lysis and
Dogs with melanoma were tration with lymphosarcoma cells. phagocytosis of marrow cells
also reported to be at risk for by adjacent tumor cells, and
developing thrombocytopenia paracrine suppression of
(35%), but this risk was partially attributed to the cy- thrombopoiesis by substances produced by the infiltrat-
toreductive therapy these dogs received.4 In other stud- ing malignancy.9–11
ies, thrombocytopenia was documented in as many as Earlier reports implicated acidic lactoferritins in
75% of dogs with hemangiosarcoma in various loca- leukemic cell extracts and conditioned media in the
tions7 and 91% of dogs with cutaneous vascular tu- suppression of myeloid colony formation in short-term
mors.8 One quarter (6 of 24) of the dogs with heman- cultures.9,12 More recent studies, however, show strong
giosarcoma died as a direct result of their hemostatic evidence that the suppressive influence of tumor cells
abnormalities.7 on marrow hematopoiesis lies in some intrinsic quality
The lowest platelet counts were associated with he- of the malignant cell itself and not in the secretion of
mangiosarcoma and melanoma (87,000 ± 41,000 and humoral factors.13 In fact, in vitro analysis of cells from
97,000 ± 56,000 platelets/µl, respectively). Mean human patients with childhood acute lymphoblastic
platelet counts in patients with lymphoma and pul- leukemia revealed that radiation-induced loss of blast
monary adenocarcinoma were moderately low cell viability did not attenuate the suppressive effects on
(120,193 ± 58,000 and 121,400 ± 55,000 platelets/µl, adjacent progenitor cell growth.13 Furthermore, control
4
respectively). lymphoblasts isolated from patients with lymphoblastic
Although boxers and golden retrievers were at in- leukemia in which peripheral pancytopenia was not
creased risk for developing neoplasia, the latter were present did not exert suppressive effects on progenitor
particularly at risk for developing thrombocytopenia.4 hematopoiesis when subjected to the same experimen-
In general, large breeds represented the greatest propor- tal protocol; however, this study did not eliminate the
tion of dogs with concurrent neoplasia and thrombocy- possibility that inhibition of hematopoiesis was exerted
topenia (55%) compared with medium (25%) or small by normal accessory cells present in the progenitor cell
(20%) canine breeds.4 cultures.13
The mechanisms of paraneoplastic thrombocytope- Regardless of the exact mechanism, most researchers
nia fall into several main categories: decreased platelet concur that hematopoietic suppression is mediated by
production, platelet destruction, accelerated platelet some change in the marrow microenvironment induced
consumption, platelet loss through hemorrhage, and se- by the presence of infiltrating malignant cells.14 Al-
questration. The historically nonstandardized approach though many dogs with lymphosarcoma (20%) have
to the characterization and therapy of paraneoplastic bone marrow infiltration without peripheral pancytope-
thrombocytopenia precludes an accurate determination nia,10 lymphoproliferative disorders (e.g., lymphosarco-
of the relative role each mechanism plays in the animal ma [Figure 1], acute leukemias,15 multiple myelomas15)
population; however, all have been documented. may result in myelophthisis as part of the natural disease
course (Figure 2).10,11 Thrombocytopenia was evident in
DECREASED THROMBOPOIESIS a dog with myelophthisic disease associated with
Attenuated thrombopoiesis has been reported in dogs megakaryocytic leukemia.16 Nonlymphoid metastatic
with myelophthisic disease, myelodysplasia, Sertoli cell neoplasias, including mammary, prostatic, and nasal
tumors or other estrogen-secreting neoplasias, and adenocarcinomas, have been associated with myeloph-
chemotherapy-associated marrow suppression. thisis in humans and infrequently in dogs.10,11

INCIDENCE ■ PLATELET COUNTS ■ MYELOPHTHISIS ■ LYMPHOSARCOMA

Small Animal/Exotics Compendium November 2000

Figure 2—Bone marrow cytology showing significant marrow Figure 3—Peripheral blood smear showing giant platelets.
infiltration with neoplastic plasma cells, easily identifiable by
their distinctive perinuclear “halo.” Although occasional neu-
trophils and nucleated erythrocytes are present, the particle is
hypercellular and more than 80% of nucleated cells are neo-
plastic.

Myelodysplastic syndromes are considered “preleu-

kemic” and are characterized by an arrested or aberrant
maturation sequence resulting in the release of blastlike
or otherwise morphologically abnormal marrow cells
into the circulation. This condition has been described
in dogs,17 cats,18,19 and horses20 but is best characterized
in humans.21 As with myelophthisis, peripheral blood
parameters reveal anemia, neutropenia, and thrombo-
cytopenia.18 Peripheral platelets may be large and ab- Figure 4A
normally shaped and/or have atypical granule con-
tent 10,18,22 (Figure 3). Marrow aspirates may reveal
normo- or hypercellularity, but abnormal progenitor
cells of any or all lineages are a consistent finding10
(Figure 4).
Estrogen toxicity is one of the more common causes
of bone marrow aplasia in veterinary medicine. Throm-
bocytopenia associated with estrogen secretion has been
documented in animals with Sertoli23 and granulosa
cell 24 tumors. Although all lineages are suppressed,
megakaryocyte progenitors are the ones most severely
affected by exogenous estrogen administration. 25,26
Myelofibrosis is a possible sequela to prolonged hyper-
estrogenism. Marrow aplasia is often refractory to treat- Figure 4B
ment despite complete tumor excision and normaliza-
Figure 4—(A) Bone marrow cytology showing megakaryocyt-
tion of estrogen levels23 (Figure 5). ic dysplasia. Megakaryocytes are normally much larger than
Although therapy-induced thrombocytopenia is doc- they appear here and have nuclei with a considerably more
umented in the treatment of canine neoplasia, chemo- lobulated appearance. Compare the two megakaryocytes in
therapy regimens employed in veterinary medicine are this figure with normal megakaryocytes (B).
not as aggressive as are those used to treat human ma-
lignancies and thus result in neutropenia far more often
than thrombocytopenia. This disparity in suppressive is exerted on predominantly committed progenitors
effects on one marrow line versus another suggests that rather than on earlier pluripotent cells.27 Differences in
hematopoietic inhibition by chemotherapeutic agents lineage sensitivities to cytotoxic agents are also implied.27

MYELODYSPLASTIC SYNDROMES ■ ESTROGEN TOXICITY ■ MYELOFIBROSIS

Compendium November 2000
Drugs reported to cause sig-
nificant thrombocytopenia
include dacarbazine, cytosine
arabinoside, cisplatin, bleo-
mycin, vinblastine,10 and in
my experience, lomustine. The
nadir is typically 9 to 10 days
after administration, which
reflects the average life span
of platelets (6 to 10 days); re-
covery occurs 7 to 10 days
later. Other more commonly
used drugs, such as cyclo- Figure 5—Bone marrow histopathology showing marrow bind, increasing the risk for
phosphamide and doxoru- aplasia secondary to estrogen toxicity.
bicin, rarely cause significant
reductions in platelet count.
In fact, certain chemotherapeutic agents (e.g., vin-
cristine) can cause thrombocytosis through the prema-
ture release of marrow platelets.
PLATELET DESTRUCTION
Another major mechanism of thrombocytopenia is
immune-mediated destruction of platelets induced by
the presence of malignant cells. Although more com-
monly associated with hematopoietic malignancies, the
syndrome has been documented in humans28 and dogs
with solid tumors, including mammary adenocarcino-
ma, mast cell tumor, hemangiosarcoma, nasal adeno-
carcinoma, and fibrosarcoma. 29 In these cases, the
pathogenesis of thrombocytopenia was characterized by
positive direct immunofluorescence staining of mega-
karyocytes using rabbit anti–canine globulin fluores-
cein-conjugated antibodies. 29 Although assays for
platelet factor 3 were also performed, this test is much
less sensitive and failed to uniformly identify immune-
mediated thrombocytopenia in patients otherwise diag-
nosed as positive. One proposed mechanism of im-
mune-mediated platelet destruction is opsonization
secondary to platelet membrane damage caused by pas-
sage through aberrant tumor vasculature. Abnormal
microvascularization has been described in heman-
giosarcomas and widespread carcinomas.30
Other proposed mechanisms include direct produc-
tion of anti-platelet antibodies by neoplastic cells them- dence of immune-mediated disease.
selves, tumor-induced production of antibodies that
cross-react with platelet antigens,29,31 and nonspecific
coating of platelets with circulating tumor antigen or
immune complexes and subsequent phagocytosis by
32
monocytes. In dogs with solid tumors, the concentra-
tion of circulating immune complexes was significantly
greater in untreated dogs than in the same dogs after
they were in remission.33 Alternatively, any proteins
that coat platelets, such as those produced by multiple
SOLID TUMORS ■ PLATELET FACTOR 3 ■ SCHISTOCYTES ■ TUMOR THROMBI
Small Animal/Exotics
myeloma cells, may predis-
pose platelets to immune-me-
diated destruction. However,
immune-mediated destruc-
tion is difficult to definitively
demonstrate because there are
no highly sensitive and specif-
ic tests to identify opsonized
platelets.
Sample handling may ex-
pose antigens to which im-
munoglobulins subsequently
false-positive results. Further-
more, patients with anti-
platelet autoantibodies may
not show hematologic evidence of platelet destruction34
(e.g., thrombocytopenia, elevated mean platelet vol-
ume, marrow megakaryocytic hyperplasia), raising
questions regarding the significance of such test results.
A bone marrow assessment for supportive evidence is
further obfuscated because platelets and megakaryo-
cytes share many of the same antigens35; lack of an ac-
celerated marrow response to thrombocytopenia may
result from an immune-mediated response directed
against megakaryocytes.36,37
Diagnosis must be predicated on a combination of
consistent findings, such as positive immunofluores-
cence studies,38 anti-nuclear antibody assays and/or lu-
pus erythematosus preparations,4 supportive clinical
hematology (thrombocytopenia, elevated mean platelet
volume, the presence of spherocytes and/or agglutina-
tion if accompanied by anemia) and consistent marrow
cytology (megakaryocytic hyperplasia), and response to
immunosuppressive therapy or splenectomy. The pres-
ence of schistocytes, for example, may be evidence of
non–immune-mediated destruction of erythrocytes and
possibly platelets. In one study assessing 214 tumor-
bearing dogs with thrombocytopenia, none were diag-
nosed with immune-mediated thrombocytopenia. 4
Very few studies have analyzed a significant number of
dogs with cancer and suspected immune-mediated
thrombocytopenia using multiple parameters as evi-
Non–immune-mediated platelet destruction includes
microangiopathic thrombocytopenia or damage caused
by the presence of tumor thrombi or associated lesions
within vascular channels.39,40 Marrow-infiltrating2,6 or
large tumors with abnormally small or tortuous blood
vessels (e.g., hemangiosarcoma, hepatic or splenic ma-
lignancies) cause fragmentation of erythrocytes and
platelets passing through their vascular beds.3,41 Platelets
may be destroyed by shearing or may be activated and
Small Animal/Exotics
subsequently consumed by tissue
factor exposed when the integrity
of endothelium is disrupted by tu-
mor cell aggregates.30 Alternative-
ly, endothelial integrity in some
tumors (hemangiosarcoma) is in-
herently aberrant and may predis-
pose to platelet activation and fi-
brin deposition. Platelets in dogs
with cancer may already be in a
partially activated state,42 increas-
ing the risk for thrombus and fi-
brin formation. Platelet activation
may in turn play a role in the de-
velopment of localized and dis-
seminated intravascular coagula-
tion (DIC).
Microangiopathic hemolytic
anemia and thrombocytopenia in
dogs are best documented in pa-
tients with heavy tumor burdens
or tumors infiltrating the bone
marrow, liver, or spleen (e.g., lym-
phoproliferative malignancies, 6 Figure 6— Hemangiosarcoma nodules in the quired membrane alterations
hemangiosarcomas2,7,43; Figure 6). spleen and omentum of a dog.
A recent prospective analysis of 24
dogs with hemangiosarcoma reported that nearly half
displayed evidence of microangiopathic thrombocy-
topenia.7 Although DIC played a role in platelet con-
sumption in many of these dogs, this study document-
ed microangiopathic hemolytic anemia without DIC in
7
12% of 24 dogs with hemangiosarcoma.
PLATELET CONSUMPTION AND LOSS
Consumptive coagulopathy, the third main mecha-
nism of neoplasia-induced thrombocytopenia, is a com-
mon and devastating consequence of many malignan-
cies. Platelet consumption may be part of an overall
syndrome of activation and depletion of hemostatic
substances, either locally (local intravascular coagula-
tion) or systemically (DIC). Alternatively, platelet ag-
gregates may form and be removed from circulation
without inducing significant involvement or imbalance
of the clotting cascade.
Shortened platelet survival has been documented in
44 5
humans and dogs with malignancy. In a study analyz-
ing platelet kinetics in dogs with cancer, 6 of 15 dogs
(40%) with localized tumors and 30 of 35 dogs (80%)
with disseminated disease had accelerated platelet
turnover.5 In this study, histologic diagnosis and extent of drome is characterized by tumor sequestration and de-
disease were determinants of platelet survival time; dogs
with adenocarcinoma, lymphoma, and sarcoma had
mean platelet survival times of 3.1, 3.2, and 3.7 days, re- ting times, and microangiopathic hemolysis induced by
DISSEMINATED INTRAVASCULAR COAGULATION ■ PLATELET LIFE SPAN
Compendium November 2000
spectively, versus 5.4 days in con-
trol animals.5 Platelet life span was
uniformly, albeit not significantly,
shorter in dogs with metastatic dis-
ease than in their counterparts with
localized malignancies of the same
histopathologic classification (3.2
versus 4.4 days). Overall, tumors
associated with the fastest platelet
turnover included advanced lym-
phoma (1.2 days) and metastatic
adenocarcinoma (2.7 days).5 In hu-
mans, remission was accompanied
by a return to normal platelet life
span.3 Mechanisms proposed to ex-
plain the reduced platelet life span
in dogs with cancer include phago-
cytosis of platelet aggregates result-
ing from direct platelet–tumor cell
interactions,10,45 platelet adherence
to newly and incompletely en-
dothelialized vasculature,10,46 and
phagocytosis of platelets with ac-
caused by adsorption of tumor-as-
sociated soluble proteins.10,47
Although more attention is being directed to the
study of direct tumor cell–platelet interactions and
their role in metastasis, intravascular coagulation, re-
gardless of origin, remains the most common cause of
accelerated platelet consumption in cancer patients.2,7,10
More recent literature defines DIC as a clinical syn-
drome of thrombosis and hemorrhage in which three of
the following five criteria are met: thrombocytopenia,
prolonged activated partial thromboplastin time and/or
prolonged prothrombin time, decreased fibrinogen
concentration, elevated fibrin degradation products,
and the presence of schistocytes on a blood smear.7 Ma-
lignancy is the most common cause of DIC in dogs.48
In 214 dogs with cancer, up to 90% with specific tu-
mor types had hemostatic abnormalities consistent with
DIC.4 The prevalence of DIC in dogs with heman-
giosarcoma is especially high, with 50%7 to 90%4 of
dogs affected. DIC was least documented in dogs with
brain tumors (0%).4
Localized intravascular coagulation has recently been
described in dogs with cutaneous hemangiosarcomas49
and may resemble Kasabach–Merrit syndrome in hu-
mans with large cavernous hemangiomas. This syn-
pletion of platelets and fibrinogen,50 consumption of
coagulation factors and resultant prolongation of clot-
Compendium November 2000 Small Animal/Exotics

The Rapid
fibrin strands and intratumoral thrombi.49,51 Laborato-
ry analysis may make differentiating this syndrome
from DIC difficult; distinguishing features may be
limited to restricted localization of fibrin thrombi to
the tumor, preferential tumor uptake of indium-la-
I Publication
Veterinary Research
I
beled platelets and fibrinogen,50 or resolution of hemo-
static parameters after surgical resection of the mass or
occlusion of its blood supply.51 Localized intravascular
coagulation associated with vascular tumors may be
Quarterly
l Issue
Inaugura

caused by platelet activation in response to exposure of e 1, Numb

er 1 •
Winter
2000

Volum

subendothelial tissue within the tumor, increased ma- -IN-CHIE

F:
, DVM,
MS,

ary
EDITOR M. Dowling
Patrici
a CVCP
M, DA
DACVI

Veterin utics
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lignant endothelial cell expression of tissue factor, plas-

B
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AL R MS,
EDITORI erson, DVM,
And
Mark ,
DACVS M, PhD
tges, DV
W. Bar
Joseph M, DA
CVN
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DACVI DVM, PhD

minogen activator or other procoagulants, or turbulent Bauer,

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John rn, PhD
Blagbu , PhD

Therap
Byron , BS, MS DVM,
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Frank Boo
Merton CVIM,
Dawn , DA
MS, PhD

blood flow and concomitant hemolysis and platelet ac- MPH,

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edicine
wn, BA,
C. Bro
Wendy CVIM
PhD w, DV
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Dennis an, DV

Applied
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tivation resulting from aberrant, tortuous vessel mor-

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Linda M, DAV PhD,
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phology.49,51,52
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Primary changes in platelet function may play a key
d, DV
d B. For
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PhD
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Effect of vitis in Dogs T.D. Yonkers,
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role in the development of DIC; humans with various Larry

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Kin
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Lesley
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Michae hrop,
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brinolysis.53 This same study concluded that the consis- DVM, ne ial Activ
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tently elevated β-thrombomodulin levels in cancer pa-

McGuirk M, MS the Ma port Viral Va
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evidence of exaggerated platelet activity.53 Michae

DACVI

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64

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William ,
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A recent study compared the results of three assays DACVA

Victori

Dennis
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Editors

Statem
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Mission

(platelet coagulant activity, total thrombin formation, DABVP M,

ite, DV
D. Wh
Stephen
DACVD

and lag time to thrombin formation) among three

groups of humans patients, each having one of the fol-
lowing diseases: myeloproliferative disorders, idiopathic
Presenting applied medical
marrow aplasia, or immune-mediated thrombocytope- information across all species
nia.54 Platelet coagulant activity is the negatively charged
surface of the activated platelet membrane providing a
and practice specialty lines
substrate for the assembly of clotting factors through
cross-linkage with calcium. This anionic charge is not ■ Canine to food animal to exotics
expressed in unactivated platelets. In the process of acti- ■ Dermatology to internal medicine
vation, however, platelets express enzymes that “flip- to behavior
flop” the membrane layers, exposing the negatively
charged surface for clotting factor adsorption. Total
thrombin formation and the time to thrombin forma-
tion are indirect measurements of platelet coagulant ac- IT’S NOT JUST
tivity. Even when corrected for size variations, platelets
from patients with myeloproliferative disorders formed THERAPEUTICS!
significantly greater thrombin, in both activated and in-
activated (basal) states, than did those from controls.54
This study corroborates earlier suppositions that
platelets in patients with neoplastic disease have tumor-
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PLATELET HYPERAGGREGABILITY ■ THROMBIN

Small Animal/Exotics
many malignant tissues express and release thrombo-
plastin-like activity, which in turn activates platelets;
whether ensuing intravascular coagulation is localized or
disseminated may depend on whether the release of this
thromboplastin-like activity is confined to the bound-
aries of the tumor or circulates systemically.56
Some tumor types produce factors that favor either
thrombosis or hemorrhage. Hemostatic abnormalities
were primarily manifested as thrombosis in 40% to
50% of humans with such solid tumors as mucinous
carcinomas, 57,58 although the overall incidence of
thrombosis in malignancy is only 15%.57,59,60 In patients
with mucinous adenocarcinomas, the mucin secreted
by tumor cells contains a sialic acid moiety that nonen-
zymatically activates factor X.61,62 Another significantly
prothrombotic malignancy is pancreatic carcinoma
(particularly of the body and tail, where outflow is not
obstructed); this tumor releases systemic trypsin, a
powerful activator of intravascular coagulation. As
many as half of all patients with pancreatic carcinoma
have thrombotic events.57,59,60
Conversely, hemorrhage is the primary hemostatic
derangement in patients with such other neoplasms as
prostatic carcinomas or acute leukemias.56 Prostatic
adenocarcinoma can activate both the procoagulant sys-
tems (which in turn activate fibrinolysis) and fibrino-
lytic systems independently, thereby tipping the deli-
cate balance between the two in favor of hemorrhage.
Hemorrhage may result not only from overexuberant
fibrinolysis but also from consumptive thrombocytope-
nia and/or platelet dysfunction. Significant hemorrhage
occurs in as many as 40% to 70% of humans with acute
leukemias; the excessive fibrinolysis documented in this
malignancy is often accompanied by defects in platelet
function, including abnormal release of platelet factor
3, and a decreased aggregation response to thrombin,
ADP, epinephrine, and collegen.56,63,64 Hemorrhage is
the primary cause of death in 40% of patients with
acute leukemias65; excessive platelet consumption with
subsequent thrombocytopenia is the most common un-
derlying risk factor.57,66
Specific procoagulant substances expressed by or as a
result of malignancies include tissue factor, tissue fac-
tor–factor VII complex, and cancer procoagulant. Tis-
sue factor, a membrane glycoprotein expressed in many
normal and malignant tissues, serves as the site for fac-
tor VII activation.67 Circulating tissue factor has been
measured in the serum and urine of cancer patients67,68
and is well documented to induce hypercoagulability.
Once activated, tissue factor–factor VIIa complex acti-
vates factor IX and the cascade continues, resulting in
the formation of thrombin, a powerful platelet activa-
tor and fibrin former.67
MUCIN ■ FIBRINOLYSIS ■ CANCER PROCOAGULANT ■ HYPERVISCOSITY SYNDROMES
Compendium November 2000
Cancer procoagulant, a cysteine proteinase that acti-
vates factor X directly, is present in tumor cell extracts
but not in cells of normal differentiated tissue.69,70 Cir-
culating cancer procoagulant is significantly elevated in
85% of cancer patients compared with non–tumor-
bearing patients.71,72 The expression of marrow cell can-
cer procoagulant activity can be serially assessed to
monitor the course of the disease because expression
rises during relapse from remission even before neoplas-
tic cells reappear.67,73 As with other procoagulants, the
excessive formation of thrombin results in fibrin forma-
tion and platelet activation. Other tumor-specific pro-
coagulants (e.g., albumin-associated fatty acids, mucin
from adenocarcinomas, procoagulant activity/platelet
activity–factor X activator) have been described, but ac-
tivities have not been confirmed.67
Cancer procoagulants are also released when tumor
cells are lysed or become necrotic. Patients with heavy
tumor burdens undergoing aggressive chemotherapy or
radiation therapy may be predisposed to thrombosis and
subsequent DIC resulting from the release of thrombo-
plastin-like substances from necrotic tumor cells.67 Ves-
sel derangement may also result in excessive exposure of
procoagulants and increased vascular permeability,
which may allow localized procoagulants to gain access
to the systemic circulation. This phenomenon may oc-
cur during vascular invasion by leukemic cells, in tu-
mors with primary endothelial dysplasias (hemangiosar-
coma), in foci of extramedullary hematopoiesis within
vessel walls, and in hyperviscosity syndromes (multiple
myeloma), in which paraprotein precipitates damage the
microvasculature.56,57,74
Although thrombosis is significantly more common in
humans with malignant tumors than in dogs with can-
cer, the incidence in animals may be underreported ow-
ing to lack of follow-up after unexplained deaths or may
be overshadowed by development of DIC. Nevertheless,
thrombosis of the iliac arteries in dogs with gastrointesti-
nal lymphomas—without any other hematologic disor-
ders—has been described in the veterinary literature.75
PLATELET LOSS THROUGH HEMORRHAGE
Hemorrhage other than that associated with a con-
sumptive coagulopathy is another mechanism predispos-
ing tumor-bearing animals to thrombocytopenia.10,76
Blood loss may occur through aberrant endothelialization
(as with hemangiosarcoma), chronic oozing from the tu-
mor surface, or infiltration of the vasculature. In these
cases, when bone marrow is functioning normally, the
marrow regenerative response tends to render peripheral
thrombocytopenia mild or unremarkable. However,
thrombocytopenia resulting from acute or severe hemor-
rhage associated with tumor rupture may be moderate to
Small Animal/Exotics
severe, especially when concurrent
consumptive processes exist (Fig-
ure 7).
Significant chronic hemorrhage
may result in thrombocytopenia
when it overwhelms the marrow’s
compensatory efforts to replenish
consumed and lost platelets. Per-
sistent hemorrhage can be caused
by defects in platelet function or
acquired von Willebrand’s dis-
75
ease. Although an in-depth re-
view of platelet function defects is
beyond the scope of this article, a
brief discussion of neoplasia-asso-
ciated platelet dysfunction is war-
ranted because the resulting hem-
orrhage may be exacerbated by
moderate thrombocytopenia. Ac-
quired von Willebrand’s disease
occurs in humans with multiple
myeloma, lymphoma, macroglob-
ulinemia, and myeloproliferative
disorders and is believed to be me- Figure 7—Thoracic radiograph of a dog with aly39,40 caused by large vascularized
diated by anti–von Willebrand’s significant hemorrhage caused by mediastinal tumors may also predispose to
factor antibodies. 77,78 Although hemangiosarcoma.
this condition has not been re-
ported in the veterinary literature, decreased platelet
adhesiveness has been reported in dogs79 and horses80
with multiple myeloma caused by coating of platelets
with paraprotein.
In one study, one third of dogs with hyperviscosity
caused by multiple myeloma, especially those which
elaborated IgA or IgM, manifested bleeding diatheses.81
The cause of the hemorrhage may have been multifac-
torial, including overdistention and mechanical rupture
of small vessels82 by paraprotein precipitates coating
vessels,56,74 decreased platelet aggregation56,57,76 and ad-
hesion resulting from adsorption of paraprotein to
platelet membranes,79 defective fibrin formation and
polymerization,83 and reduced availability of platelet
factor 3.3,10
Impaired aggregation represents the most commonly
reported platelet defect in humans with myeloprolifera-
tive or myelodysplastic syndromes.84 Other platelet de-
fects associated with these syndromes in humans and
animals include decreased adhesiveness, reduced platelet
factor 3 activity, and decreased granule stores.10,15,48,84,85
Platelets may not function normally in patients with
fulminant DIC (because of coating by fibrin degrada-
tion products) or in malignancy-associated liver and
kidney failure (because of ammonia and ure-
56,75,84,86,87
mia). Specific heparinlike anticoagulants may
HEPARINLIKE ANTICOAGULANTS ■ HYPERSPLENISM ■ STRESS PLATELETS
Compendium November 2000
be elaborated by tumors (e.g.,
mast cell tumors) that inhibit
thrombin formation and indirect-
ly attenuate platelet activation.
SEQUESTRATION
The last major mechanism of
neoplasia-associated thrombocy-
topenia is by sequestration.10 Ap-
proximately one third of total body
platelets is stored in the spleen.10,25
Therefore, any condition that in-
creases splenic blood pooling would
result in enhanced sequestration of
platelets. Infiltrative tumors caus-
ing hypersplenism can predispose
to thrombocytopenia by this
mechanism; hemangiosarcoma,7,43
hemangioma43,88 (Figure 8), lym-
phoma,5,10 feline mast cell tumor,10
and a variety of other neoplasms89
have been reported to result in
thrombocytopenia. Hepatomeg-
platelet sequestration.10 Whereas
thrombocytopenia caused by de-
struction, consumption, or hemorrhage induces bone
marrow acceleration of thrombopoiesis and release of
“stress” platelets, thrombocytopenia resulting from
platelet sequestration often does not elicit the same mar-
row response; this may reflect the influence of throm-
bopoietin (a cytokine produced by the kidneys and liver
that exerts its hematopoietic effect on megakaryocyte
progenitors) on platelet production. Although controver-
sial, many investigators hypothesize that thrombopoietin
Figure 8—Large hemangioma with 65,000 platelets/µl in a
dog. The dog recovered well clinically and hematologically
following splenectomy and was still doing well 2 years later.
Compendium November 2000
is constitutively produced and that levels are regulated
through occupation of receptors on megakaryocytes and
platelets90,91; if total body concentration of receptor-bear-
ing cells is adequate—whether sequestered or in circula-
tion—thrombopoietin remains receptor bound and un-
able to stimulate marrow precursors.
SUMMARY
Understanding the pathophysiologic mechanisms by
which thrombocytopenia develops in dogs with cancer
is paramount in developing appropriate diagnostic and
therapeutic plans. The next installment in this three-
part series will describe strategies for diagnosis and
treatment of paraneoplastic thrombocytopenia in dogs;
several case examples will be used to illustrate impor-
tant points.
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About the Author
When this article was submitted for publication, Dr.
Chisholm-Chait was affiliated with the Department of Small
Animal Surgery and Medicine, College of Veterinary Medi-
cine, Auburn University, Alabama. She is now with the Pet
Emergency and Specialty Center, La Mesa, California.