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Drug-induced thrombosis and vascular disease in patients with malignancy
Kenneth A Bauer, MD
UpToDate performs a continuous review of over 350 journals and other resources.
Updates are added as important new information is published. The literature review
for version 14.3 is current through August 2006; this topic was last changed on
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.2007
INTRODUCTION — Cancer is often associated with a state of hypercoagulability
which can have a variety of clinical manifestations including migratory superficial
thrombophlebitis, "unprovoked" deep vein and other venous thrombosis, nonbacterial
thrombotic endocarditis, and disseminated intravascular coagulation. Deep vein
thrombosis is the most common vascular toxicity of antineoplastic therapy.
Intracranial dural sinus vein thrombosis and thrombotic microangiopathies can also be
.)"seen. (See "Hypercoagulable disorders associated with malignancy
This review will discuss vascular complications caused by the various
.chemotherapeutic agents used in the treatment of patients with malignant disease
MECHANISMS AND RISK FACTORS — The proposed mechanisms for the
increased incidence of vascular complications in patients with malignancy include
release or expression of procoagulants by tumor cells (eg, cancer procoagulant and
tissue factor) and expression of procoagulant activity by normal host cells such as
monocytes, platelets, and endothelial cells. (See "Pathogenesis of the hypercoagulable
.)"state associated with malignancy
In addition, the usual treatments for cancer also significantly increase the risk of
thrombotic events. Surgery is a major precipitating factor, with the risk of
postoperative thrombosis being several-fold higher than in patients without cancer.
(See "Prevention of venous thromboembolic disease", section on Surgery in cancer
patients). High dose chemotherapy and bone marrow transplantation for hematologic
malignancies are associated with an enhanced risk of thrombosis, particularly hepatic
veno-occlusive disease. (See "Pathogenesis and clinical features of hepatic venoocclusive disease following hematopoietic cell transplantation"). A number of
chemotherapeutic regimens have been associated with an increased rate of
thromboembolism [1]. Two of the regimens most commonly complicated by
thrombosis are L-asparaginase, often given for acute lymphoblastic leukemia, and the
administration of tamoxifen and other agents in the treatment of breast cancer (see
below). The presence of an indwelling central venous catheter is a known risk factor
for the development of upper extremity venous thrombosis in both adult and pediatric
cancer patients. (See "Catheter-induced upper extremity venous thrombosis" and see
"Pathogenesis and clinical manifestations of venous thromboembolism in infants and
.)"children
Disease- and patient-specific risk factors may also contribute to the risk of
chemotherapy-associated venous thromboembolic disease. In a study of 3003 patients
receiving at least one cycle of chemotherapy, symptomatic VTE occurred in 1.9
percent over a median follow-up of 2.4 months, or a rate of 0.8 percent/month [2].
The highest rates were seen in patients with upper gastrointestinal cancers, lung
.cancer, and lymphoma, with rates of 2.3, 1.2, and 1.1 percent/month, respectively
On multivariate analysis, the following factors were significantly associated with
development of symptomatic VTE [2]: Upper gastrointestinal malignancy (odds ratio
[OR] 3.9, 95% CI 1.4-10) Pre-chemotherapy platelet count 350,000/microL (OR 2.8,
95% CI 1.6-4.9) Use of white blood cell growth factors (eg, G-CSF, OR 2.1, 95% CI
)1.2-3.6) Hemoglobin <10.0 g/dL or use of erythropoietin (OR 1.8, 95% CI 1.1-3.1
L-ASPARAGINASE — Thrombotic events have been reported with induction
chemotherapy regimens for acute lymphoblastic leukemia (ALL) that include Lasparaginase. (See "Treatment of acute lymphoblastic leukemia in adults").
Intracranial dural sinus thrombosis with hemorrhage is observed most frequently, but
deep venous thrombosis and pulmonary embolism can also occur [3-5]. In one large
series of children receiving L-asparaginase as part of induction chemotherapy for
ALL, the incidence of thrombotic complications was 1.2 percent [4]. Generalized
.bleeding episodes have rarely been observed
Asparaginase depletes plasma asparagine, thereby inhibiting protein synthesis in
leukemic cells and the synthesis of many plasma proteins. The latter effect causes
deficiencies of albumin, thyroxine-binding globulin, and various coagulation proteins,
including prothrombin, factors V, VII, VIII, IX, X, XI, fibrinogen, antithrombin,
protein C, protein S, and plasminogen [6-8]. This results in prolongation of the
prothrombin time, activated partial thromboplastin time (aPTT), and thrombin time,
and in hypofibrinogenemia with levels often less than 100 mg/dL. These coagulation
.abnormalities resolve within one to two weeks after cessation of the drug
It is difficult to assess the role of the substantial reductions in the levels of natural
anticoagulant proteins such as antithrombin, protein C, and protein S in the
pathogenesis of the thrombotic events. Both procoagulant and anticoagulant protein
synthesis in the liver are decreased by L-asparaginase, leading to uncertainty as to
whether there is an alteration in the balance of the opposing forces of the hemostatic
.mechanism. Two mechanisms have been considered
Antithrombin — There are data suggesting that antithrombin supplementation given
concurrently with L-asparaginase may suppress the prothrombotic state [9-11].
However, a drug-induced decrease in antithrombin is not predictive of subsequent
thrombosis. In one study of children with ALL receiving L-asparaginase, prednisone,
and vincristine, no correlation was found between protein C, protein S, or
.]antithrombin levels and the presence or absence of thrombosis [12
von Willebrand factor — Qualitatively abnormal von Willebrand factor (vWf) has
been found in several patients at the time of L-asparaginase-induced thrombosis [13].
L-asparaginase may lead to a transient increase in unusually large plasma vWf
.]multimers that have enhanced platelet agglutinating properties [13
Erwinia-asparaginase is an alternate preparation which may have fewer effects on the
coagulation system than Escherichia coli L-asparaginase. In a series of 11 adults with
ALL, there was significant lowering of antithrombin but the levels of the vitamin-K
.]dependent procoagulant factors II, VII, and X, remained within normal ranges [14
TREATMENT OF BREAST CANCER — A number of large studies have found an
increased incidence of thromboembolic events in women with breast cancer treated
with chemotherapy, tamoxifen, or both. Additional risk factors may include
postmenopausal status, prior mastectomy, increased body weight, presence of an
.]indwelling central venous catheter, and evidence of coagulation activation [15
Chemotherapy — Studies of adjuvant chemotherapy for stage II breast cancer or
primary chemotherapy for advanced, metastatic disease have shown a high incidence
of thrombosis, both arterial and venous, during but not after chemotherapy. The risk is
higher in patients with metastatic disease, which is probably due to the increased
tumor burden and the increased incidence of other predisposing factors such as
.immobilization
Incidence — The incidence of thromboembolic disease following chemotherapy for
breast cancer has varied widely in different reports, and appears to be related to the
stage of the disease, the chemotherapeutic regimen given (eg, CAF versus CMF), and
whether tamoxifen is given concurrently or following completion of chemotherapy
(see "Tamoxifen and raloxifene" below). In a randomized study of early breast cancer,
patients assigned to perioperative chemotherapy with fluorouracil, doxorubicin and
cyclophosphamide had a higher incidence of thromboembolic events within six weeks
after surgery than a control group treated with observation alone (2.1 versus 0.6
percent) [16]. In a Cancer and Leukemia Group B (CALGB) study, 433 patients were
randomly assigned to receive one of three regimens based upon cyclophosphamide,
methotrexate and 5-fluorouracil (CMF) as adjuvant therapy [17]. Thromboembolic
disease occurred in 5 to 7 percent. There was no difference between the three groups.
.No patient developed thrombosis after chemotherapy was completed
A similar incidence (7 percent) was noted in a prospective study evaluated of 205
women with stage II breast cancer who were treated with one of two chemotherapy
regimens: CMFVP (cyclophosphamide, methotrexate, fluorouracil, vincristine, and
prednisone) or CMFVP plus doxorubicin and tamoxifen [18]. Once again, no
thrombotic episodes occurred during 2413 patient months of follow-up without
therapy. There was no relationship between the development of thrombosis and
estrogen or progesterone receptor status, age, number of involved lymph nodes, or
subsequent tumor recurrence. A higher risk of thrombosis (18 percent) was noted in a
series of 159 patients treated with CMFVP for advanced, stage IV disease [19]. There
were no differences in the presence of risk factors for thrombosis between the patients
.who had a thromboembolic event and those who did not
Although most patients develop venous thrombosis, there is also an association
between arterial thrombosis and cancer therapy among women with breast cancer
[20,21]. A CALGB study, for example, found a 1.3 percent incidence of arterial
thrombosis, either peripheral or cerebrovascular, in 1014 patients during treatment for
stage II or III breast cancer on two separate chemotherapy protocols [20]. All but one
.of the thrombotic events occurred while patients were receiving chemotherapy
Mechanism — The mechanism of the thrombogenic effects of chemotherapy in
patients with breast cancer is not well understood. One report noted statistically
significant decreases in protein C and protein S levels during CMF chemotherapy
which, in some patients, fell below the range of values seen in hereditary thrombotic
disorders [22]. Reductions in procoagulants factor VII and fibrinogen were also
present and none of the patients in this small series had clinically evident thrombosis.
In another report, there were significant declines in protein C concentration during
CMF chemotherapy, which returned to baseline values after the completion of therapy
.][23
Possible explanations for these chemotherapy-induced abnormalities include
impairment of vitamin K metabolism and inhibition of DNA/RNA synthesis, leading
to a reduction in protein synthesis by the liver. In addition, endothelial cell injury can
lead to qualitative or quantitative abnormalities in vWf which may enhance the
thrombotic potential. Other possible mechanisms include direct platelet activation,
reduced fibrinolytic activity, and the release of procoagulant from tumor cells dying
.as a result of antineoplastic therapy
Attempts to identify patients at risk by monitoring with coagulation tests have not
been successful. In a study of 50 patients treated with adjuvant epirubicin and
cyclophosphamide chemotherapy, the incidence of deep vein thrombosis was 10
percent [24]. Preoperative levels of D-dimer, fibrinogen, and plasminogen activator
inhibitor activity were significantly higher in the patients with breast cancer than in
healthy women; however, monitoring during chemotherapy did not identify patients at
.higher risk for deep vein thrombosis
Tamoxifen and raloxifene — A number of studies, including the Early Breast Cancer
Trialists' Collaborative Group (EBCTCG) overview analysis and the large Breast
Cancer Prevention Trials, have demonstrated that tamoxifen use is associated with an
increased rate of venous thromboembolic events and that there is a significant
additional procoagulant effect when tamoxifen is added to chemotherapy [21,25-32].
In at least one randomized trial the incidence of VTE was lower when raloxifene was
used in place of tamoxifen [33]. (See "Selective estrogen receptor modulators for the
prevention of breast cancer" and see "Use of selective estrogen receptor modulators in
postmenopausal women", section on Adverse effects and see "Adjuvant systemic
therapy for hormone receptor positive early stage breast cancer in postmenopausal
women"). In the NSABP P-1 Breast Cancer Prevention Study, which involved 13,388
women followed for an average of 3.6 years, the rates of pulmonary embolism and
deep vein thrombosis were increased in older women receiving tamoxifen (risk ratio
3.0 [CI 1.1 to 11.2], and 1.6 [CI 0.9 to 2.9], respectively) [30]. In a subsequent pooled
analysis of 13 NSABP Breast Cancer Prevention trials, which involved 20,878
women, the risk of pulmonary embolism, deep venous thrombosis, and superficial
phlebitis was increased two- to threefold in those treated with tamoxifen and was
increased 11- to 15-fold in those treated with tamoxifen plus chemotherapy [31]. Risk
factors included increased age and body mass index; there were no differences in the
rates of thrombosis between African Americans and white women in this study. In the
five-year, randomized, double-blind, placebo-controlled International Breast Cancer
Intervention Study (IBIS-1), involving 7,139 patients, use of tamoxifen was
associated with an increased risk of developing a major venous thromboembolic event
(odds ratio 2.1, 95% CI: 1.1-4.1) [34]. This risk was further increased in those patients
who had surgery, immobilization, or fracture in the month prior to the event (odds
ratio 4.7, 95% CI: 2.2-10.1). Factor V Leiden and prothrombin mutations were not
associated with thrombosis in this population or in subjects participating in the
National Surgical Adjuvant Breast and Bowel Project's Breast Cancer Prevention
.]Project (BCPT) [35
The possibility that tamoxifen may be associated with an increased incidence of
stroke was raised in two NSABP randomized trials: P-1 and NSABP B-24, a trial of
tamoxifen for intraductal breast cancer. However, the available data are conflicting: In
the EBCTCG overview analysis of approximately 15,000 women randomized to five
years of tamoxifen or control, there was a trend toward increased stroke-related
mortality that did not reach the level of statistical significance (54 versus 29 deaths, p
= 0.07) [32]. Tamoxifen use was not associated with higher stroke risk in a
retrospective nested case control study of 11,045 women enrolled in a large HMO in
the Los Angeles area who were diagnosed with breast cancer between 1980 and 2000
[36]. When 179 who met the criteria for stroke were compared to 358 age and year of
diagnosis-matched controls who had breast cancer but not stroke, there was no
association between tamoxifen and stroke risk. In a systematic review of randomized
controlled trials of tamoxifen use for breast cancer management and prevention
published since 1980, the frequency of ischemic stroke during a mean follow-up
period of 4.9 years was 0.71 percent with tamoxifen versus 0.39 percent for controls
[37]. It was concluded that, although the absolute risk of stroke was small, women
with breast cancer who were treated with tamoxifen had an increased risk for
ischemic stroke (odds ratio 1.82, 95% CI 1.4-2.4) or any stroke (odds ratio 1.40, 95%
.)CI 1.1-1.7
On the other hand, the increased risks of pulmonary embolus and stroke may be
partially offset by a decreased risk of ischemic heart disease. In a case control study of
women being treated with tamoxifen for breast cancer, there was a significant
decrease in the incidence of first myocardial infarction or developing angina pectoris
compared with cancer patients not being treated with tamoxifen (odds ratio 0.4, 95%
CI 0.2-0.7) [38]. This beneficial effect may be due to the favorable effect of
.tamoxifen on lipid profiles
Mechanism — The potential mechanisms for the tamoxifen procoagulant effect have
not been identified. Tamoxifen is an antiestrogen that has weak estrogenic effects
which may contribute to its prothrombotic activity. A number of studies have
evaluated measurements of hemostasis in patients taking tamoxifen. The results have
been conflicting and no major changes have been identified [39-42]. Some reports
have found modest reductions in antithrombin and protein C [39,40], while a
prospective double-blind study was unable to find consistent tamoxifen-induced
.]changes in protein S or protein C activity [42
Other agents — Aromatase inhibitors are being used as adjuvant hormonal treatment
as an alternative to tamoxifen. The incidence of thromboembolic complications with
anastrozole was significantly lower than with tamoxifen in the ATAC trial comparing
these two agents. (See "Adjuvant systemic therapy for hormone receptor positive
early stage breast cancer in postmenopausal women" section on AIs versus
.)"tamoxifen
Second-line hormonal therapy for patients with advanced breast cancer who fail
tamoxifen includes the aromatase inhibitor formestane and the progestational agent
megestrol. In a phase III prospective randomized crossover trial, the two drugs
showed similar antineoplastic activity but the incidence of deep vein thrombosis was
significantly higher with megestrol than formestane (five in 81 patients versus 0 in 90
.]patients) [43
Prophylactic anticoagulation — Long-term anticoagulant therapy with low-intensity
warfarin may be a safe and effective method for prevention of thromboembolism in
patients with metastatic breast cancer who are receiving chemotherapy. In a
prospective, double blind study, for example, 311 patients with stage IV breast cancer
received either placebo or warfarin (1 mg PO daily for six weeks which was then
adjusted to maintain an INR of 1.3 to 1.9) [44]. Treatment was continued until one
week after the end of chemotherapy which lasted approximately six months. There
were seven thromboembolic events in the placebo group and one in the warfarin
group (4.4 versus 0.7 percent), a relative risk reduction of 85 percent. Major bleeding
.occurred in three patients, two of whom received placebo
The benefit was achieved without an increase in health care costs [45]. The cost of
providing low-intensity warfarin was calculated at $219 (Canadian dollars) per patient
but therapy led to a reduction in costs of $243 per patient, producing a small cost
.saving
In a separate study, the effect of low-intensity warfarin on markers of
hypercoagulation was evaluated in a randomized trial of 32 patients with metastatic
breast cancer who were undergoing chemotherapy [46]. Before therapy, markers of
clotting activation were increased in both groups, consistent with the presence of a
hypercoagulable state. After starting chemotherapy, markers were progressively lower
in the group receiving warfarin prophylaxis. These differences became statistically
significant after the fourth course of chemotherapy. Deep vein thrombosis occurred in
two of the 16 patients receiving placebo and in none of the 16 patients receiving very.low-dose warfarin
TREATMENT OF TESTICULAR CANCER — Major cardiovascular issues that
have been studied in connection with treatment for testicular cancer include
hypertension, dyslipidemia, early atherosclerosis and coronary artery disease,
Raynaud phenomenon, and thromboembolic events. These are discussed in detail
separately. (See "Chemotherapy-related toxicity in men with testicular germ cell
.)tumors", section on Cardiovascular and see "Miscellaneous" below
THROMBOTIC MICROANGIOPATHY — Thrombotic microangiopathies have
been associated with a number of cancer chemotherapeutic agents. This primarily
occurs with one of four regimens: mitomycin C; cisplatin with or without bleomycin;
gemcitabine; and the use of radiation and high dose chemotherapy prior to
hematopoietic cell transplantation (HCT). (See "Causes of thrombotic
thrombocytopenic purpura-hemolytic uremic syndrome in adults", section on Cancer,
.)cancer chemotherapy, and HCT
The syndrome more closely resembles the hemolytic-uremic syndrome (HUS) than
thrombotic thrombocytopenic purpura (TTP) and usually develops within weeks to
months after exposure to the drug. Detection may be delayed because chemotherapy
can produce thrombocytopenia due to bone marrow depression and renal disease,
thereby masking the presence of HUS. Affected patients typically present with slowly
progressive renal failure, new or exacerbated hypertension, and a relatively bland
.urine sediment, often occurring in the absence of clinically apparent tumor
Drug-related endothelial injury is presumed to be the initiating event. It has been
proposed that vWf multimers derived from damaged or stimulated endothelial cells
may be involved in the pathogenesis of intravascular platelet clumping. However,
there are conflicting data on the role of vWf multimers in patients with drug-induced
thrombotic microangiopathies. In one study, vWf multimeric patterns were normal
during episodes of mitomycin C-induced microangiopathy [47]. However, another
report using a superior technique for detection of multimers found abnormalities in
vWf in five of six patients [48]. The sixth patient had a three fold elevation in the
.levels of vWf antigen
MISCELLANEOUS — A variety of other drugs that can be used in patients with
malignancy can be associated with thromboembolic events: High doses of estrogens
increase the plasma concentrations of clotting factors and the risk of thrombotic
disease [49]. Estrogenic prothrombotic effects are believed to be responsible for the
dose-related cardiovascular complications of the estrogen analogue diethylstilbestrol
(DES) in the treatment of prostate cancer [50]. In comparison, the lower doses used
for hormone replacement therapy or oral contraception are associated with only a
small increase in thrombotic risk. (See "Postmenopausal hormone therapy and
cardiovascular risk", section on Venous thromboembolism). Dacarbazine, alone or in
combination with other drugs has been associated with the Budd-Chiari syndrome
[51]. In addition, veno-occlusive disease of the liver has been reported in patients with
acute myelocytic leukemia who were treated with thioguanine and daunomycin with
or without cytarabine [52,53]. Arterial ischemia or thrombosis in major coronary or
cerebral vessels and in the small vessels of the extremities can be induced by
chemotherapy. Various combinations of bleomycin, cisplatin and vinblastine are
associated with myocardial infarction and stroke [51,54,55]. In one study, for
example, cisplatin-based multiagent chemotherapy for urothelial transitional cell
carcinoma was associated with a 13 percent risk of vascular events (venous
thromboembolism, arterial thromboses, and cerebrovascular events), most of which
occurred during the first two cycles of chemotherapy [55]. In another prospective
series of 108 patients treated with cisplatin and gemcitabine for non-small cell lung
cancer, 19 had significant vascular events, including seven with lower extremity
arterial thrombosis [56]. (See "Neurologic complications of cancer chemotherapy").
An increased incidence of arterial thrombosis has been associated with the
monoclonal antibody, bevacizumab, in patients with colorectal cancer, who are being
treated concurrently with systemic chemotherapy. (See "Systemic chemotherapy for
.)metastatic colorectal cancer" section on Bevacizumab
Cardiac toxicity occurs in 1.6 to 2.3 percent of patients treated with 5-fluorouracil
[57], and myocardial ischemia and stroke occur in up to 10 percent of patients who
receive continuous infusions of the drug [58]. Induction of coronary spasm is the
presumed mechanism [57]. (See "Cardiotoxicity of nonanthracycline cancer
chemotherapy agents"). The use of cisplatin-bleomycin regimens for testicular cancer
has been associated with Raynaud's phenomenon in up to 40 percent of patients [5961]. Vasospasm presenting as painful digits and paresthesias typically occurs 10
months after starting therapy and lasts indefinitely. The cumulative dose of bleomycin
appears to be the major risk factor [61]. Raynaud's phenomenon associated with
bleomycin and vinca alkaloids also occurs in patients with AIDS-related Kaposi's
sarcoma [62,63]. (See "Chemotherapy-related toxicity in men with testicular germ
cell tumors", section on Cardiovascular). Thrombosis has been noted in a significant
percentage of patients with multiple myeloma treated with thalidomide and
lenalidomide, most often in combination with other agents (eg, dexamethasone,
doxorubicin). This subject is discussed separately. (See "Thrombotic complications
.)"following treatment with thalidomide and its analogues
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