Cancer and venous thromboembolism
Andrea Piccioli, MD, a Paolo Prandoni, MD, a Bruce M. Ewenstein, MD, b and Samuel Z. Goldhaber, MD b
Padua, Italy, and Boston, Mass.
Trousseau 1 was the first researcher to suggest an
association between cancer and hypercoagulability
when he observed episodic migratory thrombophlebitis among patients with cancer. Thrombotic complications are especially frequent in patients with
mucin-secreting adenocarcinomas, brain tumors,
and certain hematologic malignancies such as acute
promyelocytic leukemia and myeloproliferative disorders. Moreover, during the first 6 months after the
diagnosis of deep vein thrombosis (DVT), previously
occult cancer is often detected. 2 The appearance of
migratory thrombophlebitis, nonbacterial thrombotic endocarditis, or thromboses in unusual sites
such as the upper extremity, portal, or hepatic veins,
is of particular concern.
Abnormal platelet-vessel wall interactions and
enhanced secondary hemostasis predispose patients
who have cancer to thrombosis. These abnormalities
m a y be related, directly or indirectly, to the tumor or
may arise as complications of treatment. In some instances, the systemic effects of cancer affect the entire vasculature. In other circumstances, the cancer
may induce local hemostatic defects that result in
thromboses anatomically related to the tumor. This
article reviews the relation between cancer and
venous thromboembolism (VTE) and highlights some
relevant clinical implications.
PATHOGENESIS
Pathogenetic mechanisms accounting for the development of thrombotic disorders in patients affected by cancer were described by Virchow more
From %he Istituto Di Semeiotica Medica, University of Padua, and bthe
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston.
Dr. Goldhaber receives support from the National Heart, Lung, and Blood
Institute Academic Award in Systemic and Vascular Medicine (HL 02663).
Received for publication Dec. 7, 1995; accepted Jan. 10, 1996.
Reprint requests: Samuel Z. Goldhaber, MD, Cardiovascular Division,
Brigham and Women's Hospital, 75 Francis St., Boston, ~ 02115.
Am Heart J 1996;132:850~5.
Copyright © 1996 by MosbY-Year Book, Inc.
4/1/74444
0002-8703/96/$5.00 + 0
850
than a century ago. They include hypercoagulability
due to tumor cell activation of clotting, vessel wall
injury, and stasis. Several platelet abnormalities
have also been recognized.
Hyperaoagulability. Neoplastic cells can activate the
clotting system directly, thereby generating thrombin. Tumor cells can also stimulate the clotting system indirectly. For example, some tumor cells can
bind independently to factors Va and Xa, thus enhancing the rate of prothrombinase complex formation and permitting further generation of thrombin.
Direct tumor-cell activation of clotting. Tissue factor or similar thromboplastins can activate the
extrinsic pathway through interaction with factor
VIIa. Tissue factor procoagulant activity has been
identified in tumors and tumor cell lines derived
from h u m a n beings and animals. 3 It has been described in some acute leukemias 4 and in solid tumors
of the stomach, ovary, and kidney. 5
Direct factor X activation with the procoagulant
cysteine proteinase has been found in some patients
with lung, prostate, colon, breast, and kidney cancer
and with leukemia. 6, 7 Mucin-secreting adenocarcinomas are frequently associated with thrombosis
because the sialic acid moiety can cause nonenzymatic activation of factor X to its active form, factor
Xa. Consequently, adenocarcinomas of the lung,
pancreas, gastrointestinal tract, and ovary are often
associated with venous thrombosis, s
Indirect tumor-cell activation of clotting. Tumor
cells can activate systemic coagulation by stimulating mononuclear cells to synthesize and express various procoagulant substances, including tissue factor
and factor X activators. Peritoneal exudate cells and
tumor-associated macrophages in rabbits bearing
the V2 carcinoma express increased tissue factor activity. 9
Normal monocytes and macrophages can be activated by tumor cells in the presence of lymphocytes. 1° In patients with cancer, endothelial cells
m a y be activated by cytokines such as tumor necrosis factor and interleukin-1 or interleukinlike substances that may induce tissue factor production.11 A
peptide produced by a h u m a n bladder cancer cell line
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American Heart Journal
stimulates tissue factor expression in endothelial
cells. ]2
Tumor cells can secrete a peptide, vascular permeability factor, which can account for the increased
microvascular permeability found in a variety of tumors. ]3 Vascular permeability factor also induces
monocyte activation and chemotaxis across collagen
membranes and an endothelial cell monolayer. 14
Therefore, systemic activation of coagulation may
also reflect diffusion into plasma of extravascular
clotting factors derived from solid-tumor growth. 15
The enhanced clotting activation in patients with
cancer is confirmed by the demonstration of increased levels of systemic hypercoagnlability markers, such as fibrinopeptide A (FPA), prothrombin
fragment F1.2, and thrombin-antithrombin III complexes in most patients. 16 Alternatively, clinical
manifestations of increased thrombin generation
may be accentuated by the failure of counterregulatory mechanisms. For example, in patients with extensive liver involvement, there may be decreased
hepatic synthesis of antithrombin III and protein C.
Other patients with cancer may have consumption
coagulopathy or endothelial cell dysfunction that
contribute to a hypercoagnlable state.
Laboratory evaluation. The combination of increased thrombin generation and down-regulation of
endothelial cell counterregulatory mechanisms leads
to a prothrombotic state. Often this condition takes
the form of chronic and well-compensated disseminated intravascular coagulation, which is characterized by subtle laboratory features. Routine laboratory tests such as those for prothrombin time and
activated partial thromboplastin time (aPTT) may
actually be shortened because of increased levels of
circulating activated coagulation factors. The fibrinogen level is typically normal or slightly increased, as
is the platelet count. Additional tests, including
those for FPA, thrombin fragment F1.2, and thrombin-antithrombin III complexes may be useful adjuncts in the diagnosis of a hypercoagnlable state.
Fibrinopeptide A. FPA is a peptide released by
thrombin's proteolytic action on plasma fibrinogen
and thus is a marker of thrombin generation. This
marker is very sensitive for detecting intravascular
thrombin but is not specific for intravascular thrombosis, because increased FPA levels m a y derive from
extravascular sites or localized microvascular thrombosis as a consequence of infection, inflammation, or
traumatic venipuncture. Increased FPA levels accompany many types of tumor, signifying increased
thrombin generation. FPAlevels appear to be greater
in patients with disseminated malignancy than in
those with locally limited disease.!7
Piccioli et al.
851
Prothromb in fragment F ~.2. Prothrombin fragment
F1.2 is a peptide released from the amino terminus of
the thrombin moleculel during the conversion from
prothrombin to thrombin, by factor Xa cleavage.
Hanzal and Tatra is followed 76 patients with various gynecologic malignancies and 25 healthy women.
Two thirds of the patients with malignant disease
showed increased plasma F1.2 concentrations,
whereas F1.2 levels remained normal among the
control group without cancer, is
Thrombin-antithrombin III complexes. Thrombin-antithrombin III complexes are stable enzymeinhibitor complexes derived from the linkage between thrombin and its endogenous heparan sulfate
inhibitor antithrombin III. Increased concentrations
of thrombin-antithrombin III complexes indicate
increased thrombin generation and have often been
found in patients with cancer. 19, 20
Vessel wall injury. There is increasing awareness
that cancer cells can injure endothelium. In one
study, the adhesion of tumor cells to endothelinm
was evaluated in vivo by means of suspensions of
transplantable thymic lymphoma and Walker 256
carcinoma that were injected into the inferior vena
cava of mice and rats, respectively. 21 When the
endothelial lining was not injured, platelet tumor
aggregates adhered to intact endothelium. An observed separation of endothelial cell intercellular
junctions gave tumor cells access to a highly thrombogenic subendothelia] surface. If the endothelial
lining was mechanically injured, malignant cells adhered to a monolayer of platelets and fibrin in the
subendothelium. Both patterns indicated a complex
interaction among endothelium, platelets, and tumor cells. 21
Drug toxicity from chemotherapy can in some
cases be traced directly to vascular endothelial cell
damage (Table I). 22"26 Nicolson and Custead 27 described three types of drugs that can induce vascular
damage: (1) drugs that can cause immediate effects
on vascular endothelial cell integrity, such as bleomycin, carmustine (1,3-bis[2-chloroethyl)-l-nitrosourea [BCNU]), and vincristine; (2) drugs that can
cause delayed effects on vascular endothelial cell integrity, such as adriamycin; and (3) drugs that have
no apparent effects on vascular endothelium, such as
fluorouridine. Combinations of cyclophosphamide,
methotrexate, and 5-fluorouracil may cause reversible decreases in plasma levels of protein C and protein S. 2s, 29
Children with acute lymphoblastic leukemia have
been considered at high risk for thromboembolic
events when undergoing L-asparaginase chemotherapy. After administration of L-asparaginase, plasma
October 1996
852
Piccioli et al.
AmericanHeartJournal
Table I. Risk of venous and arterial thrombosis in patients with cancer during chemotherapy without prophylaxis
DVT
Authors, year
No. of patients
Type of cancer
During chemotherapy
After chemotherapy
Weiss et al., 22 1981
Goodnough et al.,23 1984
Levine eta]., 24 1988
Saphner et al.,25 1991
Levine et al.,26 1994
433
159
205
2352
159
Breast, stage II
Breast, stage IV
Breast, stage II
Breast, various stages
Breast, stage IV
22 (5%)
24 (15%)
14 (7%)
128 (5%)
7 (4%)
0
4 (2%)
0
0
0
inhibition of thrombin decreases because of a decrease in plasma concentration of inhibitors, especially antithrombin III. 3°
Venous stasis. Venous stasis--caused by immobility, venous obstruction, increased venous pressure,
venous dilatation, and increased blood viscosity-predisposes to VTE by preventing activated coagulation factors from being diluted and cleared by normal blood flow. Furthermore, hypoxic damage to
endothelial cells due to stasis may produce prothrombotic alterations, including reduced levels of
Surface-bound thrombomodulin and increased expression of tissue factor. In some patients with cancer, the degree of hypoxia is compounded by severe
anemia or cardiopulmonary disease.
Immobility in severely debilitated patients with
cancer or in conjunction with cancer surgery predisposes to venous thrombosis because it promotes
blood pooling into the intramuscular venous sinuses
of the calf. Venous obstruction due to extrinsic vascular compression may develop in patients with
bulky tumor masses. In addition, some tumors, most
notably renal cell carcinoma, display a propensity to
invade vascular structures, thereby producing intraluminal obstruction and disruption of the normal
endothelial lining.
Platelet abnormalities. Under normal physiologic
conditions, the endothelial cell lining of the blood
vessel provides a thromboresistant surface that inhibits platelet adherence a n d activation. In cancer
patients, the normal function of endothelium may be
disrupted through a variety of quantitative or qualitative defects in platelet function that predispose to
VTE.
Reactive thrombocytosis is frequently found in patients with cancer, especially those with advanced
disease of the lung, colon, stomach, ovary, or breast. 31
Thrombocytosis may be caused by spontaneous
clumping of platelets in the blood or by increased
levels of thrombopoietin, a plasma glycoprotein that
directly regulates the differentiation and maturation
of megakaryocytes. Increased thrombopoietic activ-
ity has been found in the serum of some patients with
cancer and thrombocytosis. 31-33
Thrombocytosis is also a common and in some
cases diagnostic feature of the myeloproliferative
syndromes. In these disorders, dysregulation of
thrombopoiesis arises from a clonal stem cell abnormality that produces platelets characterized by functional abnormalities. Many solid tumors demonstrate increased platelet adhesiveness and increased
platelet activation. Usually, increased platelet activation results from increased generation of platelet
agonists, principally thrombin and adenosine diphosphate.
Thrombocytopenia is also common among patients
with malignancies. It may reflect impaired generation of platelets, often brought about by irradiation
or administration of chemotherapy, or it can result
from marrow invasion by tumor cells. Thrombocytopenia in these patients also can be caused by
increased platelet consumption or by accelerated destruction or sequestration of platelets in enlarged
spleens. 34
CLINICAL IMPLICATIONS
Indications for prophylaxis
Primary prophylaxis. Because VTE is often encountered in patients with cancer, some clinicians
have proposed that all patients with cancer should
receive pharmacologic prophylaxis. However, further trials are needed before this approach can be
endorsed.
Currently, primary prevention should be considered for cancer patients in certain circumstances
such as during and immediately after chemotherapy.
A recent study demonstrated the advantage of using
warfarin 1 mg/day for the prevention of thrombotic
events in patients with breast cancer. 26 This approach appears to be cost effective. 35 Primary prevention also can be useful when central venous lines
are placed. Bern et al.36 demonstrated an advantage
to using warfarin 1 mg/day to prevent upper-extremity venous thrombosis. Finally, when the risk of VTE
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American Heart Journal
Piccioli et al.
Table II. Risk of postoperative DVT in patients with cancer
undergoing general surgery
Table III. Incidence of subsequent cancer detection in
patients with idiopathic and secondary VTE
Frequency of postoperative DVT
Authors, year
With cancer
Frequency of cancer
Withoat cancer
Authors, year
Kakkar et al., 37 1970
Walsh et al., 3s 1974
Rosenberg et a l . y
1975
Sue-Ling et al., 4° 1986
Allan e t a ] . , z~l 1983
Sasahara, 42 1984
Total
24/59 (41%)
16/45 (35%)
28/66 (42%)
12/23
31/100
9/37
120/330
(52%)
(31%)
(22%)
(36%)
38/144 (26%)
22/217 (10%)
29/128 (23%)
16/62
21/100
13/53
139/704
(26%)
(21%)
(24%)
(20%)
is increased by prolonged immobilization, trauma, or
surgery, primary prevention may be of benefit. In
patients with cancer, the risk of developing of postoperative DVT is greater than in patients with other
disorders (Table I I ) Y -42 Moreover, postoperative
pulmonary embolism in cancer patients is much
more frequent than in patients without cancer. 43
Secondary prophylaxis. "Treatment" of venous
thrombosis usually consists ofanticoagulation and can
be more precisely described as "secondary prophylaxis"
against recurrent VTE. For those patients who have
pelvic or lower-extremity venous thrombosis but who
are unable to tolerate anticoagulation, placement of an
inferior vena caval filter should be considered.
As is appropriate, patients with cancer who have
venous thrombosis rarely receive primary therapy
with thrombolysis. The limited cases in which thrombolysis m a y be considered include extension of venous
thrombosis despite intensive anticoagulation; upperextremity thrombosis in patients who have an indwelling central venous catheter, which must be
kept patent; or superior vena caval syndrome that
does not improve with anticoagulation, arm elevation, or (if a tumor is present) radiation therapy.
Thrombolysis is contraindicated in patients with
cancer who may have tumor in the brain or spinal
cord and in those with bulky disease in the chest,
abdomen, or pelvis.
Whenever possible, heparin should be administered as soon as a there is a reasonable possibility
that venous thrombosis exists. Heparin is a much
more effective anticoagulant than warfarin in patients with cancer. Ordinarily, warfarin can be initiated after a therapeutic aPTT (at least twice the
control value) has been documented. The warfarin
dose should be adjusted according to the inteimational normalized ratio (INR), which can be targeted
to 3.0. Higher INRs are needed for patients in whom
853
Aderka et al., 46
Monreal et al., 47 1988
Monreal et al., 4s 1991
Prandoni et al., 49 1992
Years of In idiopathic In secondary
follow-up
DVT
DVT
3.0
0.7
1.1
2.0
12/35
8/21
7/31
11/145
(34%)
(38%)
(23%)
(8%)
2/48 (4%)
1/73 (1%)
5/82 (6%)
2/105 (2%)
recurrent venous thrombosis develops despite this
level of anticoagulation.
In some patients, the thrombosis is completely resistant to warfarin, particularly in patients with
venous clot in more than one extremity. These patients should be treated with long-term high-dose
heparin, which can be given in one of several ways.
One approach involves the use of adjusted subcutaneous unfractionated heparin administered three
times daily. However, this strategy is time consuming, uncomfortable for the patient because of multiple injections, and yields highly variable aPTTs because of the erratic absorption and bioavailability of
unfractionated heparin. 44
An alternative approach is to use low-molecularweight heparin with once- or twice-daily subcutaneous injections. If this latter strategy is undertaken,
plasma heparin levels should be used if it is necessary to adjust the dose of low-molecular-weight heparin. A reasonable objective is a target plasma heparin level in the range of 0.3 to 0.7 units/ml measured
4 to 6 hours after injection.
A third strategy is to arrange for a continuous infusion of unfractionated heparin on an ambulatory
basis, particularly for patients receiving home hospice care. Adjustment of heparin concentrations is
greatly facilitated with this approach, and patients
are spared the discomfort of multiple daily injections
of heparin.
A population-based study in Rochester, Minnesota
found that among patients receiving anticoagulation, the presence of cancer was significantly associated with major hemorrhage and recurrent thromboembolism. Cancer was more of a risk factor for
hemorrhage and VTE recurrence than was old age. 45
Finally, the optimal duration of oral anticoagulation therapy after a first episode of VTE is unknown.
Long-term anticoagulation may be worthwhile until
it is certain that the cancer is cured. However, this
approach must be weighed against the increased cu-
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854
AmericanHeartJournal
Piccioli et al,
mulative bleeding risk, particularly bleeding into
sites of tumor.
Risk of subsequent cancer in patients with VTE. VTE
may be the first indication of malignancy in an otherwise healthy patient (Table III). 46-49 There is a
statistically significant and clinically important association between idiopathic VTE and the development of overt cancer, especially in patients with recurrent VTE.
A retrospective cohort study among consecutive
patients with a symptomatic idiopathic DVT showed
a 12% incidence of cancer detected after an initial
screening at referral. During a minimum of 18
months of follow-up, only 3% of 112 DVT patients
were newly diagnosed with cancer.5° Among patients
with VTE due to an unidentified cause, a diagnostic
examination for occult malignancy according to standard clinical practice is worthwhile. However, extensive screening, such as total-body computed tomography or magnetic resonance imaging, cannot be
recommended because available data indicate that
few new cancers are identified this way and that the
ultimate effect on survival probably is trivial. Nevertheless, further investigation is needed to assess
the utility of extensive screening for neoplasms in
patients with idiopathic VTE.
SUMMARY
Neoplastic cells can activate the clotting system
directly, thereby generating thrombin, or indirectly,
by stimulating mononuclear cells to synthesize and
express various procoagulants. Clinical manifestations of increased thrombin generation may be accentuated by down-regulation of endothelial cell
counterregulatory mechanisms, such as decreased
hepatic synthesis of antithrombin III and protein C.
Cancer cells and chemotherapeutic agents can injure
endothelial cells, thereby intensifying hypercoagulability. In addition, normal endothelial cell function
may be disrupted by various defects in platelet function.
Currently, primary prevention of venous thrombosis should be considered for cancer patients (1)
during and immediately after chemotherapy, (2)
when long-term indwelling central venous catheters
are placed; or (3) when hospitalization for cancer is
characterized by prolonged immobilization, trauma,
or surgery. Secondary prevention of recurrent venous
thrombosis usually necessitates anticoagulation. In
some patients with cancer, the condition is resistant
to warfarin, and long-term adjusted high-dose heparin is required. For patients unable to tolerate heparin or warfarin because of major bleeding problems,
placement of an inferior vena caval filter should be
considered. The diagnosis of venous thrombosis may
help to uncover previously occult carcinoma by
prompting a complete physical examination, chest
roentgenography, and mammography. However, extensive cancer screening with total-body computed
tomography or magnetic resonance imaging has not
been shown to be cost effective for patients with
venous thrombosis.
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