Thromboembolic Complications of Malignancy

Thromboembolic Complications of Malignancy

ABSTRACT: Thromboembolism affects many patients with solid tumors and clonal hematologic malignancies. Pathogenetic mechanisms include inflammatory- and tissue factor-mediated coagulation, natural anticoagulant deficiencies, fibrinolytic alterations, hyperviscosity, and activation of platelets, endothelial cells, and leukocytes. High rates of venous thromboembolism (VTE) occur with advanced pancreatic, breast, ovarian, germ cell, lung, prostate, and central nervous system cancers. Hodgkin disease, non-Hodgkin's lymphoma, myeloma, paroxysmal nocturnal hemoglobinuria, and certain leukemias also predispose to venous thromboembolism. Arterial and venous events occur with polycythemia vera and essential thrombocythemia. Central venous catheters and prothrombotic antitumor regimens augment the risk in some patients. Part 1 of this two-part article addresses pathophysiology, clinical presentations, and risk of malignancy-associated thrombosis. Part 2, which will appear in next month's issue, covers prophylaxis and treatment of these thromboembolic complications.

Over half of all adult cases of
venous thromboembolism
(VTE), including deep venous
thrombosis and pulmonary embolism,
occur in the setting of acquired, situational,
hereditary, pharmacologic,
and/or iatrogenic prothrombotic risk
factors.[1,2] Recent or active cancer
is one of the most powerful independent
and additive acquired hypercoagulable
conditions, approximating or
exceeding the attributable risks associated
with advanced age, acute infectious
illness, or a prior history of
VTE.[2] The annual incidence of VTE
among all cancer patients has been
estimated to be 0.5%, with 10- to 20-
fold higher rates among those with
advanced ovarian, breast, pancreatic,
and lung cancer, brain tumors, myeloproliferative
disorders (ie, polycythemia
vera and essential thrombocythemia),
myeloma, and those
treated with thrombogenic antitumor

Thromboembolic complications
of malignancy significantly affect
quality of life and may profoundly compromise
overall management and outcome.
Compared to VTE in individuals
without cancer, malignancy-associated
deep vein thrombosis and pulmonary
embolism are associated with longer
hospitalization times, a twofold higher
28-day mortality rate, a threefold higher
rate of readmission and/or death at
6 months, and two- to fourfold greater
risks of subsequent bleeding (on warfarin
anticoagulation) and/or recurrent
thrombosis (with or without continued
anticoagulation).[5-7] Moreover,
concurrent cancer increases the likelihood
of perioperative venous and
arterial thrombotic complications by
two- to threefold.[3]

The 1-year survival rate of patients
with cancer-associated VTE is onethird
lower than the survival rate of
cancer patients who remain thrombosis-
free (12% vs 36%), reflecting, in
part, the more advanced stage of disease
among thrombotic patients.[8]
These thromboembolic complications
translate into higher health-care expenditures[
7] and spotlight the need
for more selective, aggressive, and
cost-effective interventions in this
high-risk population.

Part 1 of this two-part review summarizes
pathophysiology, clinical
presentation, and risk of malignancyassociated
thrombosis. In part 2, which
will appear in next month's issue, we
will explore the management of
thromboembolic complications in cancer
patients, including the specifics of
prophylaxis and treatment, cost considerations,
and future perspectives.

Pathophysiology of Malignancy-
Associated Thrombosis
Venous vs Arterial Vascular Events
The prothrombotic mechanisms
that affect the vascular systems in patients
with malignancies mirror those
that are important in individuals without
cancer. In general, venous thrombosis
results from abnormalities that
affect blood flow, the integrity of the
venous endothelium and/or the hemostatic
balance of activated procoagulants,
natural anticoagulants,
fibrinolytic mediators and, in some
cases, platelets. Most acquired and
congenital prothrombotic conditions
alter those hemostatic mechanisms
and, thereby, predominantly lead to
deep venous thrombosis and pulmonary

Pharmacologic agents that inhibit
one or more steps in the coagulation
cascade, including unfractionated heparin,
low-molecular-weight heparin,
warfarin, or more specific inhibitors of
factor Xa (eg, fondaparinux [Arixtra])
or thrombin (eg, argatroban, lepirudin
[Refludan], bivalirudin [Angiomax])
are required to prevent and treat VTE.
Given the minor role of platelets in
this process, drugs that reversibly or
irreversibly inhibit platelet function
(eg, aspirin, clopidogrel [Plavix], ticlopidine,
dipyridamole) are not effective
for VTE prophylaxis or therapy.

Arterial vascular events generally
occur as a result of underlying atherosclerotic
disease that ultimately
leads to acute platelet-fibrin thrombotic
occlusion and/or downstream
emboli. In some cases, arterial emboli
originate in the heart (eg, from a
left atrial thrombus or valvular vegetations)
or, paradoxically, from VTEs
that traverse an intracardiac shunt into
the arterial circulation. Antiplatelet
agents decrease the chance of primary
and secondary atherothrombotic
complications and they may partially
reduce the risk of cardioembolic
events. Acute arterial thrombosis is
treated with systemic anticoagulants
and, in some cases, thrombolytic
agents (eg, recombinant tissue-type
plasminogen activator [tPA]).

Malignancy-associated thromboembolic
complications usually occur
in the venous system; however,
some conditions predispose to arterial
thromboemboli. Patients with polycythemia
vera, essential thrombocythemia,
and disorders complicated by
disseminated intravascular coagulation
(DIC), heparin-induced thrombocytopenia
with thrombosis, or
nonbacterial thrombotic endocarditis
(also known as "marantic" endocarditis),
are at increased risk of arterial
events.[3,4,10] In addition, a recent
retrospective cohort study observed
an overall 1.5% incidence of arterial
thromboemboli among 66,106 patients
hospitalized for malignancy and
neutropenia.[11] Interestingly, onehalf
of those arterial events involved
patients with leukemia and lymphoma,
and the annual frequency more
than doubled from 1995 to 2002.

Prothrombotic Mechanisms and
Altered Laboratory Values

The prothrombotic mediators and
mechanisms implicated in malignancy-
associated hypercoagulability are
summarized in Table 1. The presence
and severity of these abnormalities
relate, in part, to the underlying histology
and stage of disease, associated
comorbid conditions, and antitumor
treatments.[12] Importantly, some of
these mechanisms may also participate
in tumor progression by facilitating
microinvasion and metastasis. In addition,
neoangiogenesis may be stimulated
through tissue factor-induced
upregulation of vascular endothelial
growth factor (VEGF). The hypothetical
link between malignancy-associated
hypercoagulability and tumor
biology has been supported by clinical
data showing a decreased incidence of
subsequent primary cancer diagnosis
among patients with primary VTE
who received longer-duration warfarin
therapy[13] and improved survival
among a subset of cancer patients who
received low-molecular-weight heparin
for VTE prophylaxis.[14]

Alterations in routine hemostatic
laboratory markers may reflect direct
effects of cancer-associated prothrombotic
factors, activation of downstream
mediators, and/or the products
of the malignant cells themselves
(Table 1).[12,15,16] Among the most
common examples of causal association
are acute promyelocytic leukemia
and advanced gastrointestinal (GI) ad-
enocarcinomas, both of which are associated
with high rates of thrombosis
and laboratory markers of DIC (ie, elevated
fibrin degradation products and/
or D-dimer, increased prothrombin
time, increased activated partial thromboplastin
time, increased thrombin time,
decreased fibrinogen, and/or decreased
platelet count).

By comparison, patients with polycythemia
vera and essential thrombocythemia
are at increased risk of
venous and arterial thrombosis, and
endogenous platelet aggregation defects
are frequently demonstrable by
in vitro assays. The presence or absence
of qualitative platelet defects,
however, does not correlate with
the thrombotic risk observed in patients
with polycythemia vera or essential
thrombocythemia.[4] In most
patients with malignancies, routine
hemostatic assays are normal or only
nonspecifically altered, and these
findings do not predict clinical

More specialized or research-based
assays for cellular-derived and plasma
coagulation factors and hemostatic activity
detect abnormalities in subsets
of cancer patients (Table 1).[15-17]
Increased levels of tissue factor (the
major activator of factor VII), platelet
factor 4 (a marker of platelet activation),
procoagulants and/or markers
of thrombin/fibrin generation (ie, prothrombin
fragment 1 + 2 [F1+2],
thrombin-antithrombin complex, fibrinopeptide
A, and tPA), have been
observed in patients with adenocarcinomas
(particularly of the GI or genitourinary
[GU] tract) and advanced
solid tumors, and after acute thrombotic
complications or recurrent
thrombosis on anticoagulant therapy.[
17] Additional abnormalities include
antiphospholipid antibodies,
primary fibrinolysis, and decreased
activities of natural anticoagulants,
including protein S, antithrombin III
(ATIII), protein C, and/or the activated
protein C (APC) complex.[16,17]

The question of whether specific
laboratory alterations might identify
high-risk individuals who would benefit
from prophylactic anticoagulation
has been addressed in various studies.
One prospective myeloma treatment
trial observed an increased risk of VTE
among patients with acquired APC
resistance.[18] Other recent studies
have assessed coagulation markers in
cancer patients at the time of VTE
and compared those with markers in
cancer patients without VTE. These
trials have found correlations between
acute VTE and acquired APC resistance
or levels of thrombin-antithrombin
III complex (TAT), F1+2, tPA,
protein C activity, and/or von Willebrand
factor antigen.[16] Recurrent
VTE has been associated with Ddimer
and TAT levels.[17] Before
these hemostatic markers can be used
to guide thromboprophylaxis in
the clinic, confirmatory evidence is
needed from well-designed prospective
trials among patients with similar
disease types and treatment

Clinical Presentations of
Occult Malignancy in
Patients With VTE

Thrombosis may be the first clinical
sign of an underlying malignancy.
Roughly 7% to 10% of adults with
idiopathic VTE (ie, not predisposed
by an identifiable preexisting risk factor),
will be diagnosed with cancer at
the time of presentation or within the
next 6 to 24 months.[19,20] This is
especially true for older individuals.
Because the prevalence of cancer is
low in younger adults, the relative risk
of an associated malignancy is actually
highest among those under age 60.[20]
The malignancies most likely to be discovered
include non-Hodgkin's lymphoma
(NHL) and carcinomas of the
pancreas, ovary, liver, brain, GI tract,
lung, breast, and GU system.

Approximately 10% to 25% of
patients with unrecognized polycythemia
vera or essential thrombocythemia
will be diagnosed at the
time of an arterial or venous thromboembolic
event and/or will have a
history of previous thrombosis. Similarly,
up to 20% of patients with occult
paroxysmal nocturnal hemoglobinuria
(PNH), an acquired hematopoietic
clonal disorder, will present with
venous or, less commonly, arterial
thrombosis.[21] Of clinical impor-
tance, the thrombotic complications
of PNH, polycythemia vera, or essential
thrombocythemia may involve
unusual anatomic sites, such as the
hepatic veins (Budd-Chiari syndrome),
mesenteric, portal, and splenic
veins, and cerebral sinuses.

Retrospective studies and small
prospective trials have suggested that
extensive screening for occult malignancy
in adults with VTE is not beneficial
or cost-effective.[19,20] Either
routine testing was felt to be sufficient
to uncover cancer-related abnormalities
in most patients and/or
the prognosis would not have been
affected by earlier detection. However,
a more recent randomized screening
trial[22] and a prospective cohort
study[23] found that roughly half of
preexisting cancers in patients with
VTE are not detected by routine
screening (ie, a complete physical examination,
routine blood counts, blood
chemistries, urine testing, and chest
x-ray), but can be found with more
extensive studies. Prostate-specific
antigen, carcinoembryonic antigen,
CA-125, alpha-fetoprotein, abdominopelvic
imaging (by ultrasound and/or
computed tomography), or additional
imaging studies and endoscopy (as
indicated) identified the occult cancer
in 50% to 90% of cases. In addition,
many of the malignancies found with
extensive screening at the time of VTE
were at earlier stages than the tumors
diagnosed 8 to 11 months later among
patients who had undergone initial
routine testing, suggesting that some
patients might benefit from extensive

No studies have yet determined
whether extensive screening and earlier
detection of occult malignancies
in patients with VTE affect overall
prognosis and survival. The one recent
randomized clinical trial designed
to address these questions could not
complete accrual.[22] Thus, until evidence-
based guidance is available, the
clinician must be cognizant of important
clinical and laboratory indicators
to prompt additional evaluation
(Table 2).[21-23] Based on recent studies,
imaging of the abdomen, pelvis,
and chest would be an efficient next
step in the search for an occult solid

Thrombosis in Patients
With Known Malignancies

The risks of VTE among patients
with known malignancies have been estimated
by retrospective analyses of
treatment cohorts, patient registries, and
Medicare claims databases.[5,24,25]
The highest incidence rates, ranging
from 76 to 120 events per 10,000 patient
admissions, occur among patients
with ovarian, brain, pancreatic, gastric,
renal, and colorectal cancers
(Figure 1).[5] Increased incidence is
also seen with lymphoma, leukemia,
myeloma, liver, lung, prostate, gynecologic,
and breast cancers. Some retrospective
studies, but not others, have
identified advanced tumor stage (compared
to limited stage) and/or recent
chemotherapy (compared to no therapy)
as strong independent risk factors.
From the clinician's perspective, hospitalizations
for deep venous thrombosis
or pulmonary embolism most
frequently involve malignancies that
are more prevalent in the community
(such as lung, colon, prostate, and
breast cancers, leukemia, and lymphoma)
than malignancies that are most
highly thrombogenic (Figure 1).[5]

Prospective treatment trials have
provided additional important data
regarding the incidence rates of thrombosis
among patients with certain solid
tumors. The 5-year rate of VTE in
women with stage I/II breast cancer
on no adjuvant treatment is roughly
0.2%, but is fourfold or 20-fold higher
for women on tamoxifen or on chemotherapy
plus tamoxifen, respectively.
In addition, roughly 4% to 18% of
women with advanced-stage breast cancer
on chemotherapy suffer a thromboembolic
event (reviewed in [3]).
Similarly, VTE affects 11% of women
during treatment for ovarian cancer,[
26] 8% of men on chemotherapy
for germ cell cancer (especially those
with liver metastasis and receiving
high-dose corticosteroids),[27] up
to 26% of patients with malignant
glioma (especially those with lowerextremity
paresis, reviewed in [28]),
4% to 7% with lung cancer (especially
adenocarcinoma and metastatic disease),[
29,30] 2% to 25% with prostate
cancer (particularly among those
receiving estrogenic agents),[31] and
15% to 28% with pancreatic cancer
(especially those with metastatic

Among the hematologic malignancies,
roughly 6% to 13% of patients
with Hodgkin's disease or NHL develop
VTE.[33,34] Many of these
events are related to tumor-associated
vessel compression, catheter-associated
thrombosis, more advanced disease
stage, and/or earlier course of treatment.
Notably, deep venous thrombosis
and/or pulmonary embolism develop
in 60% of patients with central nervous
system (CNS) lymphoma.[35] VTE
occurs in 4.8% of patients following
stem cell transplantation for hematologic
malignancies, including 0.7% who
develop arterial events.[36] Predisposing
risks include indwelling central
catheters, line infection, sepsis, and pulmonary
disease. Recent treatment trials
for myeloma have demonstrated
VTE in 10% to 15% of patients, with
up to 35% incidence rates among some
cohorts on thalidomide (Thalomid)-
containing regimens.[37]

Polycythemia vera and essential
thrombocythemia are associated with a
5% to 10% annual risk of thromboembolic
events.[4,38] The majority of
those events affect the arterial system
(ie, stroke and myocardial infarction)
and occur most commonly in older individuals
(ie, age over 65 years) and/or
among those with a prior thrombotic
history. Thrombosis may also occur in
patients with acute leukemias and
concurrent disseminated intravascular
coagulation, especially among
those with acute promyelocytic leukemia.
Roughly 3% to 38% of patients
with acute lymphoblastic leukemia on
asparaginase (Elspar)- and/or prednisone-
containing regimens suffer
deep venous thrombosis, CNS venous
or arterial events, and catheter-related
thrombosis.[39,40] PNH is associated
with a 10-year risk of VTE
ranging from 4% to 44%, with the
highest risk among nonaplastic patients
who circulate a high proportion
of clonal PNH granulocytes.[21,41]


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