**Venous Thromboembolism and Cancer**

**A.K. Kakkar MBBS, BSc, PhD, FRCS**

Patients with malignant disease are considered to be particularly
high-risk for the development of venous thromboembolism. Not only does
thromboembolic disease complicate the cause of cancer from its
presentation through to the terminal stages of the disease, but the
prevention and treatment of thromboembolic disease in cancer is more
difficult to achieve.

Data from large epidemiological databases indicate that patients who
develop thromboembolic disease either at presentation with their cancer
or during the course of their cancer have a poorer outcome when compared
to patients with cancer who have never developed a thrombosis (1,2). The
explanation for this finding is not entirely clear. It could be that
once the cancer patient develops thromboembolic disease they are more
likely to develop recurrent potentially fatal but silent pulmonary
embolism. It may be that the systemic activation of blood coagulation
seen with symptomatic thromboembolic disease may in some way influence
the biology of the cancer since the activated coagulation proteases are
able to interact with receptors found on epithelial elements of many
cancers. Such coagulation protease receptor interactions are known to
affect the phenotype of cancers. Or it may be that the heightened
incidence of symptomatic thromboembolism in cancer patients is merely a
surrogate marker for a cancer with an aggressive biological phenotype
which will have killed the patient anyway.

Cancer patients are known to have a profound hypercoagulable state(3).
Detailed studies of haemostatic parameters in cancer patients revealed
that they have high circulating levels of the physiological initiator of
blood coagulation tissue factor and show activation of both the
extrinsic and intrinsic pathways of blood coagulation. They have marked
excessive systemic thrombin generation indicating their profound
hypercoagulablity.

About 10% of patients who present with idiopathic venous thromboembolic
disease will reveal an occult cancer within 2 years of their thrombotic
episode(4). Thus symptomatic thromboembolism maybe one of the most
important presenting features of occult malignant disease, although
there is no consensus on whether patients who had idiopathic
thromboembolism should be screened for underlying occult malignancy(5).

Patients undergoing operation for malignant disease have a heightened
risk for the development of venous thromboembolism(6). Without any
routine thromboprophylaxis rates of fatal pulmonary embolism between 1
and 5% have been reported in the literature.

In a large Californian epidemiological database analysing the frequency
of symptomatic thromboembolic disease after operative procedures at
differing anatomical locations, the presence of malignant disease was
consistently associated with a heightened risk for the development of
venous thromboembolism(7).

Non-surgical cancer patients have been much less well investigated with
regard to their risk for the development of venous thromboembolism. The
best investigated population are women with breast cancer. In this
population advancing stage of the disease, post menopausal status, and
the combination of cytotoxic chemotherapy with hormonal therapy
(Tamoxifen) was associated with an increasing risk for the development
of venous thromboembolism(8).

For other tumour types there is much less consistent data available in
the literature which describes the rates of thromboembolic disease
prospectively in populations receiving chemotherapy. Cancers such as
ovarian are associated with a 10% rate of VTE(9), primary brain
malignancy with rates between 7 and 24%(10,11), haematological
malignancies appear to have a lower frequency(12,13). The type of
therapeutic intervention may have an influence with novel biological
therapies potentially carrying a higher risk for the development of
venous thromboembolism when used in combination with cytotoxic
chemotherapy.

With regard to preventing thromboembolic disease in cancer patients, the
best investigated population are patients undergoing surgical
intervention for their cancer. Low dose unfractionated heparin is
effective in preventing both deep vein thrombosis and fatal pulmonary
embolism in general and oncological surgical patients undergoing
laparotomy. A landmark study published some 30 years ago, The
International Multicentre Trial, 4121 patients undergoing surgical
intervention 23% who underwent the operation for cancer were randomised
to a control group or to perioperative low dose unfractionated heparin.
The frequency of autopsy proven fatal PE in the cancer sub population
was reduced from 1.6% in the control group to 0.4% in the low dose
unfractionated heparin group. However, low dose heparin therapy is
associated with a small but significant increase in the frequency of
wound haematoma(14).

More recently the low molecular weight heparins have been evaluated in
large prospective clinical trials with regard to their ability to reduce
the frequency of fatal PE(15). By randomising over 23000 patients on low
dose unfractionated heparin given 3 times daily and low molecular weight
heparin once daily in the perioperative period were equally effective in
reducing the frequency of post-operative fatal PE(15). Over 6000
patients in that study underwent operation for cancer. The frequency of
fatal PE confirmed an autopsy in lung cancer patients was 0.09% but was
over three times as great in cancer surgical patients (0.33%) despite
the use of heparin based prophylaxis(16). The same study provided the
opportunity to evaluate the impact of operation for cancer on
perioperative haemorrhagic complications. It was able to demonstrate
that cancer itself is a risk factor for the development of perioperative
bleeding complications independent of pharmacological thromboprophylaxis
type.

Prophylaxis in the ambulant cancer patient receiving chemotherapy out of
hospital has not been well investigated. A single study in the
literature evaluated low intensity oral anticoagulation with the
vitamin-K antagonist Warfarin. This trial randomised woman with advanced
breast cancer and demonstrated an 85% reduction in the frequency of
symptomatic venous thromboembolism. However, the use of vitamin-K
antagonists in patients with disseminated malignancy especially to the
liver often causes concern because of the difficulty in achieving safe
consistent anticoagulation(17).

Cancer patients admitted to hospital not undergoing surgical
intervention should be treated as other acutely ill hospitalise medical
patients and provided with thromboprophylaxis based upon either the low
dose unfractionated heparin or low molecular weight heparin(18).

The use of routine anticoagulation for patients with central venous
catheters remains controversial. Historic studies suggest that the use
of low dose warfarin or low molecular weight heparin is associated with
a benefit in reducing the frequency of thrombosis associated with
central catheters.(19,20) However contemporary studies with the same
agents fail to demonstrate a benefit(21,22). This may due to the fact
that catheters are made of less thrombogenic material than in the past
and greater attention is paid to preventing low grade sepsis in lines
which may be associated with thrombosis.

Once cancer patients develop a first episode of venous thromboembolism
they are at three times the risk of developing subsequent episodes than
non-cancer patients with thrombosis and twice as likely to develop
bleeding complications on anticoagulant therapy as treatment for their
thrombosis(23). Controversy remains about how thrombosis is associated
with malignancy should be treated and in particular how secondary
prevention for recurrent thromboembolism should be provided. One option
may be the extended use of low molecular weight heparins beyond the
initial phase of thrombosis treatment(24). This has been assessed in a
single study to date where a 52% reduction in the frequency of recurrent
thrombosis in favour of patients receiving long-term low molecular
weight heparin was demonstrated(25).

A further spin off of low molecular weight heparin therapy in cancer
patients may be a potential anticancer effect for these agents. Four
contemporary clinical trials(26,27,28,29) have demonstrated that low
molecular weight heparin therapy to a greater or lesser extent may
prolong survival in patients with a mixed group of solid tumours. These
studies suggest that patients with a better prognosis may have the
greatest benefit to low molecular weight heparin exposure. The
mechanisms for this benefit remain unclear however they may be in some
part due to a prevention of potentially fatal thromboembolic disease,
neutralisation of the activated coagulation proteases that are able to
interact with numeric expressed coagulation protease receptors with
subsequent intracellular signaling and modification of chemo phenotype;
maybe due to direct cellular effects of heparin particularly in terms of
angiogenesis and apoptosis or due to the anti adhesive and anti
inflammatory effects of heparins.

Cancer remains one of the most important causes for venous
thromboembolism. Its prevention and treatment is particularly
complicated in patients with malignant disease. Thromboembolism appears
to be associated with a poorer overall outcome for cancer patients.
Exposure to anti thrombotic drugs maybe associated with an enhanced
survival with or without the presence of thrombotic disease in cancer
patients.

**References**

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