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One of the problems confronting researchers in this field is the variety of risk factors
at play in these cases: advanced age, surgery, immobility, the presence of central venous
lines and sepsis are all independent risk factors for DVT. However, different types of
cancer are associated with different VTE incidence rates, suggesting that the malignant
cells may be having a direct effect. Early reports suggested that the cancers most
frequently associated with DVT were lung and pancreas in males and gynaecologic,
colorectal and pancreatic tumours in females. This led to the view that mucin-producing
tumours were most likely to be responsible (29) and work has subsequently taken
place attempting to identify mechanisms. It is known that when monocytes interact
with malignant cells, various factors including tissue necrosis factor, interleukin-1
and interleukin-6 may be released. These cause endothelial cell damage, sloughing and
produce a pro-thrombotic surface (30). In addition, several cancer cells constituents are
known to be pro-thrombotic, such as tissue factor and cysteine proteases. However, more
recently it has been suggested that the true incidence of cancer-associated DVT merely
parallels the incidence of the specific cancer type itself (26).
Many chemotherapeutic agents are pro-thrombotic. Tamoxifen undoubtedly
increases the risk of VTE, although the mechanism is unknown. Regimes containing
platinum, asparaginase, high dose fluorouracil and mitomycin are associated with VTE.
It is thought these may also act by direct endothelial cell damage. Thalidomide, used for
multiple myeloma, is also associated with an increased incidence of VTE. This drug has
been shown to affect endothelial cell function as reflected by changes in thrombomodulin
levels (an endothelial anticoagulant mechanism) (31). Hormones and cytokines (G-CSF
and estrogens) increase the risk of VTE disease.
Surgery
The association between surgery and thrombosis is the most extensively researched. The
Worcester DVT study reported that 19% of patients with a first episode VTE had surgery
as a predisposing event (6). Similarly, Nordstrom et al. reported surgery within 30 days
to be a predisposing factor in 15% of confirmed DVT cases (5). The risk of postoperative
VTE is increased by pre-existing risk factors (i.e., age, malignancy, personal or family
history of VTE, thrombophilia or obesity). Surgery in the following circumstances was
most frequently involved: trauma, orthopaedic, abdominal and genitourinary. This has
led to the hypothesis that direct trauma to the veins may be the precipitating event,
aggravated by immobility induced by anesthesia. Although local factors may be
implicated in some cases, it should be noted that approximately one-third of DVTs after
hip replacement occur in the contra-lateral limb. Furthermore, a high incidence of DVTs
have been reported 3 weeks after discharge from hospital, in hip replacement patients
who were venogram negative at discharge (32). Not surprisingly, these data suggest
a continuing pro-thrombotic change to the clotting system, and that this risk may
continue for up to three months. The greatest period of risk is during the first week, and
the thrombus is thought to be precipitated by the combination of immobility and surgery-
related trauma.
Obstetrics
VTE is the leading cause of maternal death in western communities (33). The rate of
non-fatal VTE is difficult to determine, as many cases remain undiagnosed. However, the
ante-natal incidence of obstetric VTE, in women younger than 35 years of age, has been
reported as 0.6 per 1000 pregnancies and double this figure (1.2/1000 pregnancies) in
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those aged more than 35 years. The incidence of post-natal VTE, in these two age ranges
was 0.3/1000 pregnancies and 0.7/1000 pregnancies, respectively (34). Although ante-
natal VTE is more frequent, it is the post-natal period, due to its relative brevity, which
carries the greatest risk.
There are some important differences between pregnancy associated VTE and
other forms of this disorder. Almost 90% of DVT cases in pregnancy occur in the left
leg, compared to 55% in other situations (35,36). This is thought to be due to
compression of the left iliac vein by the right iliac artery which crosses it, and further
occluded by the gravid uterus. Furthermore, approximately 70% of pregnancy
associated DVTs are ileo-femoral, compared to only 9% in non pregnant cases (37).
This is likely to have major importance clinically as these proximal DVTs embolise
more frequently.
DVTs associated with pregnancy fulfill all of Virchov’s triad of venous stasis,
hypercoaguability and endothelial damage. In normal pregnancy there are increases in
the procoagulant factors F VIII, von Willebrand factor, and fibrinogen concentration;
a reduction in fibrinolytic activity due to increased levels of placental plasminogen
activator inhibitors; and an acquired resistance to activated protein C, a natural
anticoagulant. These changes are thought to be a physiological preparation for the
hemostatic challenge of delivery and are detectable by the twelfth week of gestation.
These pro-coagulant changes increase gradually throughout pregnancy, reaching a peak
immediately prior to the onset of labor and taking approximately 6 weeks to return to non
pregnant levels (38). The timing of pregnancy-associated VTE appears to parallel these
changes with 52% of ante-partum DVTs occurring in the third trimester (39). Damage to
the venous endothelium may occur during vaginal delivery or caesarian section, the latter
associated with further increase in the incidence of VTE.
Additional risk factors for pregnancy-related VTE are similar to the non pregnant
state. These include obesity, family or personal history of thrombosis, and
thrombophilia.
Hormone Therapy
The relative risk of VTE associated with the use of oral contraceptives containing O
50 mg estradiol (first and second generation OC) has been estimated to be four-fold
(40,41). It was assumed that reducing the concentration of estrogens would reduce this
incidence (third generation oral contraceptive tablets), but this has not been observed.
Several case control studies have indicated a similar risk with OC containing 30–40 mg
estradiol (42,43).
Oral contraceptives containing the progestins levonorgestrel and gestodene are
similarly associated with an increased risk of venous thrombosis, although some
publications on this issue have been conflicting. Nevertheless, a survey of such reports
indicated a six- to nine-fold increased risk compared to non users (44).
Hormone replacement therapy has also been shown to be associated with VTE
(45). A large number of studies have shown a relative risk, compared to non-users, of
between 3- and 4-fold, irrespective of the type of estrogen or progestin used, or
whether taken orally or transdermally. This risk is similar to that observed with oral
contraception, despite a much lower dose of estrogens administered, raising further
doubts as to whether a dose relationship exists between the estrogen and the risk of
VTE. With both oral contraception and hormone replacement therapy, the risk of VTE
appears to be greatest over the first one to two years of administration and to take at
least three months to abate.
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Travel
The link between seated immobility and venous thrombosis was first suggested by
Simpson in1940 who examined cases of fatal PE in those who had spent the night in air-
raid shelter deck chairs during the blitz (46). The issue was raised again 14 years later
by Homans who published five case reports of DVT after prolonged sitting: four of
these had traveled (2 by car and 2 by plane), while the fifth case had been to the theater
(47). Various case series, of increasing size, were published over the next two decades,
including one which introduced the completely erroneous name of “economy class
syndrome” (48). Sarvesvaran, who performed autopsies on sudden death cases at
Heathrow airport, was able to demonstrate a highly significant difference in rates of
PE between those who had recently disembarked, compared to those who were waiting
to board (49). In a similar study, Lapostolle, working at Charles de Gaulle Airport, but
with PE cases who survived, was able to correlate the incidence of cases with distance
traveled (50). All of these studies helped to confirm the existence of this association, but
not the strength or magnitude.
Since then, the issue has been clarified by two types of studies. First, prospective
studies of travelers, undergoing some kind of VTE diagnostic test both prior to and
following long haul flights. These have demonstrated a surprisingly high incidence of sub-
clinical DVT in this group, ranging from 1% (51) to 10% (2).
Second, large case-control studies comparing groups with VTE and controls for
recent travel (52–54). Although control groups have differed, and sometimes been
criticised, these studies have tended to show a small increased relative risk (w2-fold)
of VTE in long-haul travelers, when taking the whole traveling population into account.
A much higher RR (w15-fold) was observed when other risk factors (such as thrombo-
philia, past or family history of venous thrombosis, malignancy or estrogen use) were
also present.
This is an extremely interesting and important area of research as it is a risk which
applies to a very large proportion of the general population. It is estimated that 1.7 million
passengers board a plane in the United States daily, and approximately 5 billion world-
wide, annually. This population does not usually carry the co-morbidities associated with
hospital patients.
Medicine
Medical patients have been shown to be at risk of venous thrombosis (55). The highest
incidence of post-mortem PE (in patients dying in the hospital) was found in medical
patients (56). It is clear that these medical patients are frequently subject to an
accumulation of other risk factors, mentioned above: increasing age, immobility,
malignancy (either overt or occult), and inflammation. To this list may be added
categories in which the threat of VTE is even greater. Not surprisingly, patients with
enforced immobility, such as the very ill or following strokes or spinal cord injury, are
included. Approximately 5% of early deaths in stroke patients are attributed to PE (57).
Many studies have shown that heart failure is also frequently associated with VTE.
Ferrari reported a 28% incidence of congestive cardiac failure in DVT patients in whom
no other cause was found (58). Not only are VTE frequently found in medically ill
patients, but the strength of the pro-thrombotic risk is also high. The Medenox trial,
examining the use of low-molecular weight heparin as thromboprophylaxis in this group
of patients, found that the standard surgical thromboprophylactic dose (enoxaparin 20 mg
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daily) was ineffective. A higher dose (40 mg), used in orthopaedic surgery was required
to show benefit (59).
ROSENDAAL’S MULTICAUSAL MODEL AND RECURRENCES
In 1996 Prandoni et al. reported a 30.3% recurrence rate of DVTs over an eight years
follow-up (60). Kearon et al. selecting only patients without clear precipitating causes for
their VTE, found a recurrence rate of 27.4% per patient year (61). Subsequent studies have
confirmed these findings, demonstrating a cumulative recurrence rate of approximately
6% per annum, extending for at least five years.
All of the individual risk factors described above have demonstrated an additive
effect if yet other risk factors are present. For instance, long-haul travelers taking the oral
contraceptive, cancer patients with central lines, pregnancy and obesity, almost any risk
and Factor V Leiden mutation. These examples confirm the value of Rosendaal’s
multicausal model, which describes the often seen accumulation of multiple risk factors
to the point when a clinically apparent VTE develops (11). The usefulness of this model is
in the assistance it gives in deciding degrees of thrombo-prophylaxis required, or duration
of treatment, in individual cases. In those instances in which a VTE was precipitated by an
obvious and potent factor (i.e., caesarean section, hip replacement surgery or long-haul
travel) the risk of recurrence appears to be low once the precipitating factor has been
removed (62). The corollary also appears to be true. In those patients who suffer a VTE
with no apparent risk factors (sometimes called “spontaneous”) the multicausal model
predicts that there must exist underlying risk factors (probably in the coagulation system
and probably long-term). This is reflected in clinical practice with a very high incidence of
recurrence in these patients.
The challenge is to determine the strength of the associations discussed above,
the mechanisms of action, and most importantly, the interactions between such risks.
Various authors have discussed a risk scoring system. Unfortunately this requires a
better understanding of the clotting system, as well as an array of expensive laboratory
testing.
KEY POINTS
† Many of the causes of VTE may be anticipated from Virchov’s triad, which
attributed intra vascular thrombosis to an abnormality of blood flow, blood
constituent, or vessel wall.
† It is important to distinguish subclinical DVT from clinically overt cases
when considering the epidemiology of VTE.
† The incidence of VTE in the whole population has been estimated to be 10
per 10,000 per annum.
† The incidence of VTE increases exponentially with age, and there are
ethnic variations in this incidence.
† VTE acts as a multicausal phenomenon, often requiring several risk factors
to coincide for a clinically significant venous thrombosis to occur.
† The plasma thrombophilic abnormalities appear to interact with all other
clinical risk factors for VTE.
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13
Venous Thromboembolism and
Malignant Diseases
Paolo Prandoni and Andrea Piccioli
Department of Medical and Surgical Sciences, University of Padua, Padua, Italy
Anna Falanga
Department of Haematology–Oncology, Ospedali Riuniti, Bergamo, Italy
Thromboembolism is a well-recognized complication of malignant disease. Clinical
manifestations vary from venous thromboembolism (VTE) to disseminated intravascular
coagulation, more commonly observed in patients with haematological malignancies and
those with widespread metastatic cancer, to arterial embolism, more commonly observed
in patients undergoing chemotherapy and in those with non-bacterial thrombotic endo-
carditis. This overview will focus on the relationship between cancer and VTE.
PATHOGENESIS OF THROMBOSIS IN CANCER
Cancer growth is associated with the development of a hypercoagulable state in the host.
Patients with malignancy without thrombosis commonly present with abnormalities
in laboratory coagulation tests, demonstrating an ongoing process of fibrin formation and
removal at different rates (1). Importantly, fibrin and other clot components play a role not
only in thrombogenesis but also in tumor spread and metastasis (2). Histopathology studies
have long demonstrated the presence of fibrin or platelet plugs in and around many types
of tumors (3), suggesting a local activation of blood coagulation and an involvement
of clotting mechanisms in the growth of malignant tissues.
Prothrombotic Mechanisms
The activation of blood coagulation in patients with cancer is complex and multifactorial (4).
General prothrombotic mechanisms are related to the host response to cancer and include
the acute-phase reaction, paraprotein production, inflammation, necrosis, and hemodynamic
disorders. Procoagulant effects are also exerted by anticancer therapies (i.e., chemo or radio-
therapy). However, a prominent role is played by tumor-specific clot promoting mechanisms
represented by the prothrombotic properties expressed by tumor cells themselves. These
properties are unique to the malignant state.
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Malignant cells are able to activate blood coagulation in multiple ways, as follows:
(1) producing procoagulant, fibrinolytic, and proaggregating activities; (2) releasing
proinflammatory and proangiogenic cytokines; and (3) interacting directly with host
vascular and blood cells, i.e., endothelial cells, leukocytes, and platelets, by means of
adhesion molecules.
Procoagulant, Fibrinolytic, and Proaggregating Activities
Tumor cell produce their own procoagulant factors, among which the most studied are
Tissue Factor (TF) and Cancer Procoagulant (CP) (5). TF, the primary activator of normal
blood coagulation, forms a complex with Factor VII to proteolytically activate Factors
X and IX. In normal vascular cells, TF expression is tightly controlled, so it normally is not
expressed, but is induced by inflammatory stimuli, such as the cytokines interleukin-1b
(IL-1b), tumor necrosis factor-a (TNF-a), and bacterial lipopolysaccharides. In malignant
cells, however, TF is constitutively expressed. Differently, CP is a cysteine proteinase that
directly activates Factor X independently of FVII, and has been found in tumor cells and in
amnion-chorion tissues but not in normal differentiated cells. TF and CP have been
identified in several human and animal tumor tissues (6). The evidence that the resolution
by all-trans-retinoic acid of the severe coagulopathy of patients with acute promyelocytic
leukemia is associated to a parallel loss of cellular procoagulants from bone marrow blast
cells, strongly supports a role for tumor procoagulants in the clotting complications of
malignancy (7).
Tumor cells can express all proteins regulating the fibrinolytic system, including the
urokinase-type and tissue-type plasminogen activators (u-PA and t-PA), PA inhibitors
(PAI-1 and PAI-2), and PA receptor (u-PAR) (8). The increase in plasma levels of PA
inhibitors and impairment in plasma fibrinolytic activity in patients with solid tumors
represent another tumor-associated prothrombotic mechanisms.
Tumor cells induce platelet activation and aggregation by a direct cell–cell contact
or by releasing soluble factors, such as ADP, thrombin and other proteases (9). Circulating
activated platelets expose on their surface the activation-dependent antigens P-selectin and
CD63, and upon aggregation release their granule contents. Further, they increase their
capacity to interact through specific adhesive mechanisms with endothelial cells,
leukocytes, and blood borne tumor cells.
Tumor Cell-Derived Cytokines
Tumor cells produce and release various cytokines, including TNF-a, IL-1b and vascular
endothelial growth factor (VEGF), which can be involved in the onset of thrombotic
disorders of cancer patients (10). The major targets of tumor-derived cytokines are
the vascular endothelium and leukocytes. TNF-a and IL-1b induce the expression of
endothelial TF, and down-regulate the expression of thrombomodulin, the endothelial
surface high-affinity receptor for thrombin, that complex thrombin to activate the protein
C anticoagulant system. Taken together, TF up-regulation and thrombomodulin down-
regulation lead to a prothrombotic condition of the vascular wall. The same cytokines
highly stimulate the production of fibrinolysis inhibitor PAI-1, thus impairing the
endothelial antithrombotic response. Tumor-derived VEGF also induces TF expression by
endothelial cells, with implications for TF in tumor neovascularization (11). Finally,
cytokines induce changes in endothelial cell adhesion molecule expression, increasing the
capacity of the vessel wall to attract leukocyte and platelets and promoting localized
clotting activation and fibrin formation.
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Similar to endothelial cells, monocytes are activated by tumor cells and/or tumor
cell products to express TF on their surface (12). Tumor-associated macrophages
harvested from experimental and human tumors express significantly more TF than
control cells, and circulating monocytes from patients with different types of cancer show
increased TF activity. Tumor cytokines also attract and activate polymorphonuclear
leukocytes (PMN), which release reactive oxygen species and intracellular proteases that
possess several activities on endothelial cells and platelets, modifying the hemostatic
balance towards a prothrombotic state (13).
Cell–Cell Interactions
The presence of cell adhesion molecules on the surface of tumor cells warranties the
possibility to directly interact with the host cell. During the hematogenous spread, this
interaction occurs with endothelial cells, platelets, and leukocytes. The tumor cell capacity
to adhere to both resting and cytokine-stimulated endothelium is well described and
adhesion molecule pathways specific to different tumor cell types have been identified
(2,4). Malignant cells attached to the vessel wall promote localized clotting activation and
thrombus formation, and favour the adhesion and arrest of leukocytes and platelets by
releasing their cytokine content. Cancer cells also directly activate platelets, adhere and
migrate through the vessel wall and are assisted by PMN in their interaction with
endothelial cells.
Prothrombotic Mechanisms and Tumor Progression
Tumor-specific prothrombotic properties may contribute to the process of tumor growth
and dissemination. The formation of thrombin, the final effector enzyme of the clotting
cascade, and fibrin, the final product of the activation of blood coagulation, represent
coagulation-dependent mechanisms of tumor progression. In addition to that, tumor
prothrombotic properties can interfere with the malignant process by coagulation-
independent mechanisms. Relevant in this setting is the emerging role of the non-
coagulant activities of TF (2), particularly TF capacity to modulate VEGF expression
by malignant cells and normal vascular cells. This property regulates tumor neo-
vascularization and provides an important link in cancer patients between activation of
coagulation, inflammation, thrombosis and cancer growth and metastasis (14).
EPIDEMIOLOGY AND RISK FACTORS OF THROMBOEMBOLISM
IN CANCER PATIENTS
Since the initial observation by Armand Trousseau in 1865, numerous studies have
addressed the relationship between cancer and venous VTE. VTE is either a frequent
complication incancer patients, or sometimes acts as an epiphenomenon of a hidden cancer,
in such a way offering opportunities for anticipated cancer diagnosis and treatment (15).
In patients with malignancy VTE represents an important cause of morbidity and mortality.
It has been calculated that one of every seven hospitalized cancer patients dies due to
pulmonary embolism (PE) (16). Of these patients, 60% have localized cancer or limited
metastatic disease, which would have allowed for longer survival in the absence of a fatal
PE. According to the Medicare Provider Analysis and Review Record database that records
Venous Thromboembolism and Malignant Diseases 157
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