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Cancer, Coagulation, and Anticoagulation

ANTHONY LETAI,a,b DAVID J. KUTERa
a
Hematology-Oncology Department, Massachusetts General Hospital Cancer Center, Boston, Massachusetts, USA;
b
Dana-Farber Cancer Institute, Boston, Massachusetts, USA

Key Words. Cancer · Heparin · Warfarin · Coagulation · Thrombosis · Pulmonary embolism · Small-cell · Chemotherapy · Breast

A BSTRACT
Thromboembolic disease affects about 15% of cancer heparin (unfractionated and low molecular weight), war-
patients and presents a challenge to the oncologist for both farin, and internal vena cava filters. The appropriate use
prophylaxis and treatment. Although long known to be of these therapeutic options in cancer patients is reviewed

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associated with malignancy, the underlying biochemical
mechanisms are poorly understood. Both low-dose war-
farin and low molecular weight heparin are effective
strategies for prophylaxis of venous thromboembolism,
including those involving venous access devices. Current
treatment options for venous thromboembolism include
herein. There is suggestive evidence that heparin may be
superior to warfarin in the long-term treatment of venous
thromboembolism. Whether anticoagulants might also
improve cancer survival rates independent of their effect
on thromboembolism deserves further investigation. The
Oncologist 1999;4:443-449

INTRODUCTION disease: alteration in blood flow, damage of endothelial cells,

One of the most frequent hematological complications
encountered by the practicing oncologist is disordered coag-
ulation. Thromboembolic disease affects approximately 15%
of all cancer patients [1]. This includes superficial and deep
venous thrombosis, pulmonary emboli, thrombosis of venous
access devices, as well as arterial thrombosis and embolism.
It is the second leading cause of death for cancer patients [2],
although obviously in many of these patients, thromboem-
bolic disease represents only one of many complications of
the end-stage patient.
In this paper we will focus on the hypercoagulable states
associated with cancer and the role of chemotherapy in
inducing thrombosis. We will review the problem of central
venous catheters and their associated thrombotic risk in can-
cer patients. We will describe aspects of treatment of throm-
boembolic disease which are peculiar to cancer patients and
focus on the relative roles of coumadin, heparin, and low
molecular weight heparin (LMWH) in this treatment.
Finally, we will summarize the data concerning the use of
anticoagulants as antineoplastic agents.
THROMBOPHILIA OF MALIGNANCY
Cancer and its treatment can affect all three arms of
Virchow’s classical triad of causation of thromboembolic
and elaboration of procoagulants. Cancer can affect blood
flow by mechanical effects on blood vessels near a tumor.
Also, the angiogenesis induced by many tumors causes the
creation of complexes of blood vessels that are aberrant in
appearance and have very disordered flow. In fact, flow in
these vessels can vary not only in magnitude, but also in
direction. Endothelial cells can also be damaged directly by
tumors or chemotherapy.
Procoagulants can be increased on the surface of cancer
cells, and may also be secreted into the blood stream by can-
cer cells [3]. Examples of molecules elaborated by cancer
cells that can predispose to disordered coagulation include
tissue factor, a Vitamin K-dependent cysteine protease that
activates factor X, and a mucin procoagulant that activates
prothrombin. Furthermore, chemotherapy treatment can
cause a reduction in levels of the anticoagulant proteins C
and S. Indwelling venous access devices may also predispose
to thrombosis by altering blood flow, damaging endothelial
cells, and serving as a surface upon which procoagulants can
promote thrombosis.
In addition, other factors can cause dysregulation of the
normal mechanisms of thrombosis and hemostasis. Certain
tumors cause thromboembolism by direct extension and
blockage of neighboring vessels. The best-known example

Correspondence: Anthony Letai, M.D., Ph.D., Dana-Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA.
Telephone: 617-632-6077; Fax: 617-632-5822; e-mail: aletai@partners.org Accepted for publication October 31, 1999.
©AlphaMed Press 1083-7159/00/$5.00/0

The Oncologist 1999;4:443-449

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444
is probably renal cell carcinoma, which can be associated
with internal vena cava (IVC) thrombus by direct extension
of tumor into this vessel. Long-term survival of patients
with this disorder has been reported after complete resec-
tions of the tumor and thrombosed vessel, sometimes even
including the right ventricle.
Other tumors are associated with a secondary thrombo-
cytosis [4]. However, there is not an association of this
thrombocytosis with activation of the clotting cascade or clin-
ical thromboembolism. Tumor cells may activate platelets in
yet other cases. It is hypothesized that the resulting platelet
aggregation may assist in the implantation of metastases, and
perhaps even in protection from the host immune system.
CHEMOTHERAPY AND THROMBOSIS
Chemotherapy itself can increase the risk of thromboem-
bolic disease. This has been best studied in breast cancer
where tamoxifen and cytotoxic chemotherapy both appear
independently to increase the risk for venous thrombosis
[5-10]. The increase in risk appears to be greatest in post-
menopausal patients. An increased risk for arterial thrombosis
has also been observed [7, 11]. It should be noted, however,
that many of the chemotherapy regimens in these studies con-
tained more drugs (up to seven) than are typically present in
today’s one, two, or three-drug regimens.
It is reasonable to ask if there is an effective strategy to
prevent thrombosis in breast cancer patients receiving
chemotherapy. Perhaps the best data are from a British study
in 1994 [12]. Three hundred and eleven metastatic breast can-
cer patients receiving “first or second-line” chemotherapy
were enrolled within four weeks of initiating the chemother-
apy. One hundred and fifty-nine received a sham pill and
sham internationalized normalized ratio (INR) in a double-
blinded fashion. One hundred and fifty-two received low-
dose warfarin at 1 mg daily for six weeks; after six weeks, the
warfarin dose was adjusted to attain an INR between 1.3 and
1.9. Patients were screened with an ultrasound if they had
symptoms of venous thrombosis. A positive ultrasound find-
ing was confirmed by venography. There was a statistically
significant difference in thrombotic events between these
groups. In the placebo arm, there were six deep venous throm-
boses (DVTs) and one pulmonary embolus (PE); in the war-
farin arm, there was one PE. There was no difference in
bleeding events between the arms; there were two major
bleeding events, one fatal, in the placebo arm and a single
nonfatal bleeding event in the warfarin arm. There was no dif-
ference in survival between the groups.
Because of concern that the benefit in preventing nonfa-
tal thromboembolic events did not justify the expense and
labor involved in giving low-dose warfarin, a follow-up
study in 1995 estimated that low-dose warfarin would be not
Cancer, Coagulation, and Anticoagulation
only cost-effective, but also cost-saving [13]. The amount
saved was estimated to be 2,443 Canadian dollars per 100
patients. Based on this study, low-dose warfarin may be an
option for patients who are receiving breast cancer
chemotherapy and do not have a contraindication. However,
such a practice has not been widely adopted in the USA. It is
important to see if a simpler regimen of warfarin at 1 mg per
day would also be effective. Such a regimen would certainly
be even cheaper and more convenient and could be easily
applied to patients receiving chemotherapy for other cancers.
Another drug that is commonly associated with derange-
ment of coagulation is L-asparaginase, used almost exclusively
in the treatment of acute lymphoblastic leukemia. This drug
effects the depletion of L-asparagine, which in turn inhibits pro-
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duction of many plasma proteins, including fibrinogen, plas-
minogen, antithrombin III, protein C and protein S. Thrombotic
complications often manifest as stroke or seizures, arise in 1%-
14% of patients treated [14]. Unfortunately, since hemorrhage
is also a potential complication of this drug, prophylactic anti-
coagulation is not employed. Adminstration of antithrombin III
(AT III) has been shown to correct laboratory abnormalities,
but has not been shown to affect clinical outcomes. As depleted
fibrinogen can lead to bleeding, many physicians follow fib-
rinogen levels on patients treated with L-asparaginase and
transfuse cryoglobulin if levels fall too low. Recent evidence
indicates that patients with inherited defects in coagulation,
such as Factor VLeiden AT III deficiency, are at significantly
increased risk of thrombosis due to L-asparaginase [15].
INDWELLING CENTRAL LINES AND VENOUS
THROMBOSIS
Patients with cancer often receive central venous access
catheters for administering chemotherapy, blood products, flu-
ids, medicines, and also for drawing blood for diagnostic tests.
There is good evidence that these create an increased risk for
DVT of the ipsilateral upper extremity. Although rates of
symptomatic thrombosis are lower, clots have been veno-
graphically documented in 38%-62% of venous access devices
[16, 17]. Several factors have been identified that may influ-
ence the risk of thrombosis. Left subclavian lines are at higher
risk than the right [18]. Polyvinyl chloride or polyethylene
lines are more likely to lead to PE than are polyurethane or sil-
iconized lines [19]. A triple lumen catheter may be more
thrombogenic than a double lumen. A line requiring two punc-
tures for insertion was more thrombogenic than those placed
with a single puncture. Finally, the type of fluid infused
through the line may affect the thrombosis rate: infusion of
total parenteral nutrition fluid has been found to be more
thrombogenic than infusion of crystalloid fluid [20].
Upper extremity DVTs (UEDVT) can indeed give rise to
PE. Asymptomatic cancer patients with indwelling central
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Letai, Kuter
lines were screened with ultrasound to look for UEDVTs. In
those with positive results, a nuclear ventilation/perfusion
(V/Q) scan was then obtained regardless of whether the patient
had symptoms of PE. Of 86 patients with UEDVT, 13 (15%)
were considered to have PE by a high-probability V/Q scan
[19]. Four of the 13 had signs or symptoms of PE. Of note, two
of the 13 ultimately died of massive PE despite anticoagulation
with heparin. In a study of patients (only a minority of whom
had cancer) presenting with symptomatic UEDVTs, PE was
found in 36% (8 of 22), based either on a high-probability lung
ventilation/perfusion scan or pulmonary angiography [21].
Other investigators found that the relative risk was 3.4 when
PE from catheter-related UEDVT was compared with other
causes of UEDVT [22].
UEDVTs associated with indwelling catheters are there-
fore common and carry with them a significant risk for PE as
well as the local morbidity associated with the thrombosis.
Additionally, such thrombosis may lead to other costly proce-
dures to clear or replace the central line. Are these DVTs pre-
ventable? In a randomized, prospective trial, Bern and
coworkers demonstrated that 1 mg per day of warfarin is a
safe and effective prophylaxis against thrombosis in cancer
patients with central venous catheters [16]. Consecutive can-
cer patients receiving portacaths placed by surgeons were
enrolled. If they had no contraindications to anticoagulation,
they were randomized to receive either 1 mg per day of war-
farin or no drug. Warfarin was initiated three days prior to the
placement of the portacath. The distribution of cancers in both
arms was similar. In those receiving warfarin, four out of 40
(9.5%) had thrombi; in the 40 patients who did not receive
warfarin, 15 out of 40 (37.5%) had thrombi (p < 0.001).
Similar results have been obtained in a study of British cancer
patients receiving central venous lines [23]. A LMWH (dal-
teparin, Fragmin®) also demonstrated benefit in preventing
central catheter-associated thrombosis in cancer patients in a
randomized, prospective trial [17].
Taken together, these studies show: A) UEDVT is com-
mon in cancer patients with indwelling lines; B) pulmonary
embolus is a significant risk of these DVTs, and C) 1 mg per
day of warfarin is a safe, cheap, and effective way to reduce
the risk of UEDVT. Anticoagulation of indwelling central
lines should be considered in all cancer patients who do not
have a specific contraindication.
TREATMENT OF THROMBOEMBOLIC DISEASE IN
CANCER PATIENTS
Should the treatment of thromboembolic disease be any
different for cancer patients than it is for noncancer patients?
One concern is that cancer patients who are anticoagulated
might have an increased risk of hemorrhage due to tumor,
thrombocytopenia, or concurrent coagulation disorders.
445
Retrospective studies do not provide a clear answer. Some did
not find coexistent malignancy to be a risk factor for major
hemorrhage during anticoagulation [24, 25] while some did
[26]. In a prospective cohort study, cancer patients who
received warfarin for the treatment of DVT and/or PE were no
more likely than controls to have hemorrhage [27, 28]. A sec-
ond concern is that compared to patients with nonmalignant
disease, cancer patients are more likely to have a recurrence
on warfarin or after warfarin is stopped [29-32]. Some authors
suggest that instead of anticoagulating for 6-24 weeks for a
first DVT, cancer patients need to be anticoagulated until
there is no evidence of disease. Therefore, in treating a can-
cer patient with thromboembolic disease, the oncologist
faces a situation where there may be a slightly greater risk
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of hemorrhage, but also a greater risk of recurrent throm-
bosis. In most nonmoribund cancer patients, anticoagula-
tion for thromboembolic disease is usually begun unless
potential contraindications exist.
Special conditions may be present which might present a
relative or absolute contraindication to anticoagulation.
Oncologists are often confronted with a patient with a brain
tumor who requires anticoagulation for a DVT. There has
been a long-standing reluctance to treat these patients with
therapeutic anticoagulation due to the fear of intracranial
hemorrhage. An alternative therapy that has been used is an
IVC filter. There are no good prospective randomized studies
to evaluate the relative safety and efficacy of IVC filter place-
ment versus anticoagulation in this setting. A retrospective
series can give us only rough estimates of efficacy and com-
plication rates. The chance of recurrent PE after IVC filter
placement is in the 3%-20% range [33, 34] and the rate of
local thrombotic complication (IVC clot, DVT progression,
recurrent DVT, or postphlebitic syndrome) ranges from 5%-
57% depending on the series [33-37]. For comparison, the
risk of thromboembolic events in similar patients treated with
anticoagulants was 5%-20% [33, 36, 38]. The risk of intra-
cerebral hemorrhage, the main concern of most clinicians in
anticoagulating patients with brain metastases, was 0%-5%
[33, 35, 38, 39]. In general, bleeding complications occurred
in the setting of supratherapeutic anticoagulation. In sum-
mary, there are not enough data to make a definitive recom-
mendation for therapy in the setting of a patient with both
thromboembolic disease and brain metastasis. However, anti-
coagulation is a noninvasive, inexpensive, reversible inter-
vention that has the advantage of treating the underlying
clotting diathesis present in many of these patients. Although
they reduce the PE risk, IVC filters do not correct the under-
lying coagulation defects and may themselves undergo
thrombosis with its consequent lower extremity morbidity.
This latter complication makes IVC filters an unattractive but
sometimes unavoidable option.
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446
Because they are highly vascular, renal cell and
melanoma metastases to the brain are held in special regard
by many clinicians, as these can have spontaneous hemor-
rhage. However, no trials have studied their risk of bleed-
ing during anticoagulation. Until further safety information
is available, anticoagulating patients with these metastases
to the brain should be avoided.
HEPARIN VERSUS WARFARIN
Does long-term heparin therapy afford any advantage over
warfarin in the treatment of thromboembolic disease in cancer
patients? No prospective randomized trial has compared
heparin with warfarin for the treatment of thromboembolic dis-
ease. However, in an extensive retrospective analysis of
patients with Trousseau’s syndrome, a condition in which
recurrent, migratory thromboembolism is found in patients
with adenocarcinoma, it was found that 19% of patients bene-
fited from warfarin therapy while 65% benefited from heparin
therapy [40]. In a more recent retrospective review, cancer
patients treated with warfarin for their first venous thromboem-
bolism (VTE) had a recurrence rate of 22% within three months
in contrast to those treated with heparin (standard or low mole-
cular weight) who had a recurrence rate of 7% [32]. The clini-
cal experience of many practicing oncologists also supports this
impression. There are also anecdotal reports of patients with
Trousseau’s syndrome responding well to LMWH, which
allows for their convenient outpatient treatment.
On a biochemical level, heparin has several antithrom-
botic mechanisms that warfarin lacks. Heparin can release tis-
sue plasminogen activator and tissue factor pathway inhibitor
(TFPI) from endothelial binding sites and increase their cir-
culating levels. TFPI is a tri-domain protein that binds to the
complex formed by tissue factor, factor VIIa, and factor X
and suppresses the generation of Xa by tissue factor [41].
Heparin (both unfractionated and low molecular weight), but
not warfarin, can increase the circulating amount of this pro-
tein and also increase its specific activity. Since tissue factor
is an important stimulus to coagulation in cancer patients,
activation of TFPI by heparin may contribute greatly to the
overall antithrombotic effect of heparin.
Despite the impressive biochemical and retrospective
clinical data already mentioned, there are no prospective
clinical studies that address whether heparin is better than
warfarin in the treatment of the first thromboembolic event in
the cancer patient. Given the availability of LMWH and the
added incentive of outpatient treatment for many of these
VTE, a study comparing three to six months of warfarin ver-
sus three to six months of LMWH in cancer patients with
VTE should have high priority.
Recurrent VTE in cancer patients on anticoagulant therapy
is not uncommon. Prandoni [29] showed that recurrent VTE
Cancer, Coagulation, and Anticoagulation
in oncology patients was 1.72 times more likely than for
patients without cancer. There are no clear clinical data to
guide the response to this situation. If a cancer patient has
recurrent thromboembolism while on therapeutic doses of
warfarin, the oncologist has three choices: A) continue war-
farin at a higher target INR; B) switch to continuous intra-
venous unfractionated heparin or intermittent subcutaneous
LWMH, or C) put in an IVC filter.
LMWH
A recent addition to the anticoagulant armamentarium in
the USA is LMWH. LMWH is prepared by chemical or enzy-
matic degradation of unfractionated heparin. Three LMWH
preparations are currently available in the USA: enoxaparin
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(Lovenox®), dalteparin (Fragmin®), and ardeparin
(Normiflo®). Compared with traditional unfractionated
heparin, LMWH has a narrower range of molecular weight
distribution; unfractionated heparin contains molecules in the
5,000-30,000 dalton range, compared with LMWH molecules
that are clustered in the 2,000-8,000 dalton range. LMWH is
readily and consistently absorbed from a subcutaneous
administration and has low serum protein and cellular binding
which produces a bioavailability of over 85% compared with
15% for unfractionated heparin. LMWH is primarily excreted
by the kidney with an elimination half-life of 3.5-4.5 h com-
pared with 1.5 h for unfractionated heparin. The high
bioavailability and longer half-life allow for twice-a-day or
even daily dosing schedules based on weight to maintain ther-
apeutic anticoagulation. Standard measurements of anticoag-
ulation such as the partial thromboplastin time (PTT) are not
usually prolonged and need not be regularly followed. If one
does wish to evaluate the extent of anticoagulation with
LMWH, an assay measuring the level of inhibition of factor
Xa activation must be obtained. A level between 0.4-0.7 is
generally considered therapeutic, but must be measured
against a standard curve constructed using that specific
LMWH.
There are now many reports which have demonstrated
that LMWH is at least as safe, effective, and cost-effective as
unfractionated heparin in treating deep venous thrombosis
and even nonmassive PE in the general population [42-46]. In
a prospective trial that randomized patients to unfractionated
heparin or enoxaparin, analysis of the subgroup of patients
who had cancer demonstrated that, as in the overall group,
enoxaparin given twice a day was as effective as unfraction-
ated heparin in the prevention of recurrent venous throm-
boembolism [47]. A retrospective analysis of the cancer
patients participating in a number of trials comparing the
safety and efficacy of unfractionated heparin and LMWH has
also demonstrated a trend toward a mortality benefit indepen-
dent of bleeding of recurrent thromboembolic disease in those
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Letai, Kuter
cancer patients receiving LMWH [48, 49]. While intriguing,
this finding must be validated in a prospective fashion to
affect meaningfully the management of thromboembolic dis-
ease in cancer patients. In any case, LMWH offers the oncol-
ogist the opportunity to treat the majority of uncomplicated
DVT cases safely, effectively, and cost-effectively at home.
In the future, home LMWH treatment may also extend to the
cancer patient with uncomplicated PE as well.
ANTICOAGULANTS AS ANTICANCER THERAPY
A final issue is whether anticoagulation provides any
benefit in treating the underlying malignant disease. In vitro
studies show that warfarin, heparin, fibrinolytics, and even
antiplatelet agents inhibit tumor growth and metastasis
[50]. Thrombin and fibrin have been found to contribute to
the adhesion and implantation of tumor cells, so antifibrin
or antithrombin agents might exert their effects by inhibit-
ing this implantation. Furthermore, heparin has been found
to inhibit vascular endothelial growth factor, tissue factor,
and platelet-activating factor, each of which may contribute
to angiogenesis. It has also been hypothesized that fibrin
deposits around tumors may offer protection against immune
surveillance, so that anticoagulants might aid in immune
clearance of small deposits of cancer cells. Although there are
many hypotheses for in vitro antitumor activity of anticoagu-
lants, the practical question is whether anticoagulants affect
cancer mortality in a clinical setting.
The use of anticoagulants as an adjunct to cytotoxic
chemotherapy has been studied in patients with small-cell lung
cancer (SCLC). In a prospective randomized trial centered in a
VA hospital, patients were given radiation therapy and
chemotherapy for SCLC, and randomized to receive either
warfarin or no anticoagulant therapy [51, 52]. The warfarin
dose was targeted to give a prothrombin time twice that of con-
trol. Patients with either extensive or limited-stage cancers
were enrolled. There was a statistically significant prolonga-
tion of survival demonstrated for those patients who received
warfarin (median survival 49.5 weeks) compared with those
who did not (median survival 23.0 weeks). Response rate
was not significantly affected, but survival and time to
relapse were. A follow-up study looking at warfarin as an
adjunct in the treatment of prostate, colorectal, head and
neck, and non-SCLC showed no survival benefit in these
relatively chemotherapy-insensitive tumors [52].
In 1989, Cancer and Leukemia Group B (CALGB)
described a trial randomizing patients with extensive stage
SCLC to one of three arms [53]. Arm 1 received MACC
(methotrexate, adriamycin, cytoxan, CCNU); arm 2 received
MACC plus warfarin (PT 1.5-2 times control); arm 3
received alternating MEPH (mitomycin, etoposide, cisplatin,
hexamethylmelamine) and MACC. There was a statistically
447
insignificant (p = 0.14) overall survival advantage for arm
2 with similar advantageous trends for the warfarin arm for
partial response, complete response, and failure-free sur-
vival (FFS). There was a statistically significant difference
(p = 0.027) in overall response rate of 67% versus 51%
favoring the warfarin arm.
In 1997, the CALGB published a study of warfarin added
to a combination of ACE (adriamycin, cytoxan, and etoposide)
and PCE (cisplatin, cytoxan, and etoposide) in the treatment
of limited-stage SCLC patients [54]. The warfarin arm
showed a survival benefit that did not reach statistical signifi-
cance (p = 0.12). The survival curve plateaus were not,
however, superimposable. Responders to chemotherapy
who received warfarin had greater than twice the survival
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time (33 month versus 13.75 month, p = 0.05).
Another study examined the utility of subcutaneous
unfractionated heparin as an adjunct to chemotherapy in the
treatment of extensive and limited-stage SCLC. The heparin
was administered in two or three daily subcutaneous doses
starting at 500 U/kg/day, and adjusted to keep the PTT at two
to three times the control value. Heparin was given for five
weeks. The heparin-treated group experienced an increase in
complete response (37% versus 23%, p = 0.004) as well as an
increased median survival (317 versus 261 d, p = 0.01) [55].
In this study as in the others, anticoagulant was administered
only near the time when chemotherapy was given. Despite the
relatively short period of anticoagulation, benefits of
improved survival were realized months to years later. This is
analogous to the situation in venous thromboembolism,
where the benefits of early short-term heparin therapy can be
realized as a decreased rethrombosis rate many months later.
These results, obtained in a prospective, randomized fash-
ion, suggest that there may be some survival benefit to anti-
coagulation in the treatment of SCLC. The effect is probably
not large, judging by the difficulty in reaching statistical sig-
nificance in the CALGB studies, but there does appear to be
a consistent small benefit. The administration of low levels of
anticoagulant is, in general, much less toxic and expensive
than the addition of another chemotherapy agent, or the use of
high-dose chemotherapy with stem cell support. While
intriguing, however, the data are not sufficiently convincing
to alter current clinical practice. With the introduction of the
LWMH, there is renewed interest in determining whether
anticoagulation may improve survival in oncology patients.
CONCLUSIONS
Thromboembolic disease is a frustrating and common
complication of malignancy. The biochemical basis of the
thrombophilia of malignancy is poorly understood and studies
to unravel its cause and relationship to the underlying malig-
nancy are sorely needed. Current treatment for DVT and PE in
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448
cancer patients includes heparin, warfarin, and sometimes IVC
filters. The last option is usually reserved for those patients
who are not candidates for anticoagulation. Since heparin pro-
vides some additional antithrombotic effects that warfarin
lacks, it will be important to study whether LMWH may be
better than warfarin in the long-term treatment of venous
thromboembolism. Furthermore, there is suggestive evidence
that warfarin and heparin may actually enhance cancer sur-
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