Platelets, Coagulation and Cancer: Multifaceted Interactions

Abstract

Approach: Literature review of the multifaceted interactions between platelets, coagulation and cancer. Results: Over the years, the links existing between cancer development, progression and occurrence of metastasis on one side and coagulation on the other have become obvious. Tumors seems to activate platelets whereas, platelets, on the other hand, through their capacity to activate and release soluble factors and microparticles, interact with tumor cells and influence immune regulation. They appear to be key regulators of many cancer events. Furthermore, coagulation with its different facets also interplays and significantly crosstalks with malignancy. The objectives of this article are to review the mechanisms through which cancer interacts with platelets and the coagulation, triggering thrombosis and the role played by platelets and coagulation factors in the regulation of cancer and to underline the perspectives that are now open in the development of novel diagnostic tools and new cancer treatment strategies. Conclusion/Recommendations: Challenging issues and unresolved questions still need to be addressed to understand the complexity existing between coagulation factors and platelet components and the different stages of cancer progression. Recent discoveries are leading clinicians to consider new therapeutic applications of anticoagulant therapies or new drugs targeting specific platelet functions in cancer patients' management. Furthermore, markers of coagulation and platelet activity may prove to serve as biomarkers for dormant tumors.

Full text

American Medical Journal 3 (2): 130-140, 2012
ISSN 1949-0070
© 2012 Science Publications
Corresponding Author: Goubran, H.A., Saskatoon Cancer Centre and College of Medicine, University of Saskatchewan, Canada
130
Platelets, Coagulation and Cancer: Multifaceted Interactions
1
H.A. Goubran and
2
T. Burnouf
1
Saskatoon Cancer Centre and College of Medicine, University of Saskatchewan, Canada
2
Human Protein Process Sciences (HPPS)-Lille, France
Abstract: Approach: Literature review of the multifaceted interactions between platelets, coagulation
and cancer. Results: Over the years, the links existing between cancer development, progression and
occurrence of metastasis on one side and coagulation on the other have become obvious. Tumors
seems to activate platelets whereas, platelets, on the other hand, through their capacity to activate and
release soluble factors and microparticles, interact with tumor cells and influence immune regulation.
They appear to be key regulators of many cancer events. Furthermore, coagulation with its different
facets also interplays and significantly crosstalks with malignancy. The objectives of this article are to
review the mechanisms through which cancer interacts with platelets and the coagulation, triggering
thrombosis and the role played by platelets and coagulation factors in the regulation of cancer and to
underline the perspectives that are now open in the development of novel diagnostic tools and new
cancer treatment strategies. Conclusion/Recommendations: Challenging issues and unresolved
questions still need to be addressed to understand the complexity existing between coagulation factors
and platelet components and the different stages of cancer progression. Recent discoveries are leading
clinicians to consider new therapeutic applications of anticoagulant therapies or new drugs targeting
specific platelet functions in cancer patients’ management. Furthermore, markers of coagulation and
platelet activity may prove to serve as biomarkers for dormant tumors.
Key words: Cancer, thromboses, coagulation, platelets and metastasis
INTRODUCTION
The objectives of this article are to review the
mechanisms through which cancer interacts with platelets
and the coagulation, triggering thrombosis and the role
played by platelet and coagulation factors in the regulation
of cancer and to underline the new perspectives that are
now open in the development of novel diagnostic tools and
new cancer treatment strategies.
I-Clinical facts: venous thromboembolism
manifestations in cancer: The most clearly established
relationship existing between coagulation and cancer is
evidenced by the frequent complication of Venous
Thromboembolism (VTE) in cancer patients. Indeed,
VTE may represent its first clinical manifestation, often
antedating any clinically objective sign of the
malignancy itself (Baron et al., 1998; Sorensen et al.,
1998). Migratory superficial thrombophlebitis was first
described by Trousseau (1865) as forewarning of an
occult visceral malignancy and his sign, known as
“Trousseau’s syndrome”, is almost synonymous to
occult malignancy (Varki, 2007). Ironically, he reported
a similar finding in himself, when he developed a
gastric cancer two years later. Greenwell (1991) and
Sack et al. (1977) extended the term Trousseau’s
syndrome to include chronic disseminated intravascular
coagulopathy associated with microangiopathy,
verrucous endocarditisand arterial emboli in patients
with cancer, often occurring in the context of making-
positive carcinomas. In recent times, the term has been
ascribed to any kind of coagulopathy occurring in the
setting of any type of malignancy (Varki, 2007).
There is a statistically significant and clinically
important association between idiopathic venous
thrombosis and the subsequent development of clinically
overt cancer, especially among patients in whom VTE
recurs during follow-up. About 10% of patients presenting
with unprovoked - idiopathic thrombosis are diagnosed
with cancer within a few years (Prandoni et al., 1992).
Even more, during the first year, the incidence of cancer in
these patients is as high as 2.1-4.6%, (Baron et al., 1998;
Sorensen et al., 1998; Prandoni et al., 1992) with an
incidence at its peak within the first 6 months (Nordstrom
et al., 1994). Approximately 40% of those cases are
already presenting metastasis at the time of diagnosis
(Baron et al., 1998; Sorensen et al., 1998; Nordstrom et
al., 1994). Cancer diagnosed at the same time as or within

Am. Med. J. 3 (2): 130-140, 2012
131
one year after an episode of VTE is associated with an
advanced stage and a poor prognosis (Sorensen et al.,
2000). Epidemiological estimates show that the annual
incidence of VTE in cancer patients may be as much as
1:200/year compared to ≈70-113 cases/100,000/year in the
general population (Silverstein et al., 1998). A large Dutch
population-based case control study of 3220 patients found
that the Overall Risk (OR) of VTE was significantly
increased in patients with malignancy (adjusted OR 6.7)
and even more so in patients with metastasis (adjusted OR
19.8) (Blom et al., 2005). The highest risk was observed in
patients with lung cancer (Odds Ratio (OR): 22.2),
hematological malignancies (OR: 28.0) and
gastrointestinal cancer (OR: 20.3) (Blom et al., 2005).
There was a moderately increased risk in patient’s ovarian
cancer (OR: 3.1; 95%CI: 0.6-15.3) and prostate cancer
(OR: 2.2; 95%CI: 0.9-5.4). The risk is enhanced by
anticancer therapy, such as surgery and chemotherapy.
Thrombocytosis could reflect inflammation but is
considered by some as a paraneoplastic phenomenon
(Estrov et al., 1995). Its presence warrants thorough
investigation for the presence of severe underlying
disease, most complicated pyogenic infections,
inflammatory rheumatic diseases and malignancy.
Moreover, thrombocytosis is a marker for major
complications and is an independent predictor of
mortality in hospitalized patients for non-malignant as
well as malignant conditions (Tchebiner et al., 2011).
The evidence of a relationship between cancer and
VTE was, understandably, used to attempt to develop
diagnostics tools. Many screening strategies to identify
occult or overt malignancies including testing for tumor
markers and advanced imaging have been applied to
patients with unprovoked VTE (Monreal et al., 2004).
However, for the time being, these offer questionable
predictive value (Nordstrom et al., 1994) and may not
be cost-effective.
In spite of such failures, there is an urgent need to
identify reliable markers of cancers, presumably based
on the identification of early hemostatic markers of
activation of the coagulation cascade conferring a
specific pattern for malignancy. The findings in this
field may pave the way for the development of
commercially available diagnostic kits capable to
identify cancers at an early phase.
Interactions between hemostasis factors and cancer
cells: The interactions between components of the
hemostatic system and cancer cells are multifaceted and
complex. The physiological mechanisms of thrombus
promotion in malignancy include some general
responses of the host to the tumor (acute phase,
inflammation, angiogenesis) and specific interactions of
tumor cells expressing Tissue Factor (TF), with the
clotting/fibrinolysis systems and with blood
(leukocytes, platelets) or vascular cells. It is still
difficult to rank the relative weight of these multiple
interactions only on the basis of the well-recognized
clinical evidence of enhanced thrombotic episodes in
tumor patients (Donati and Falanga, 2001).
There is currently renewed increasing scientific
evidence that the coagulation system and the activation
of platelets play an instrumental role in the progression
and regulation of malignant growth and facilitation of
metastasis. Important molecular crosstalk occurs
between platelets, leukocytes, endothelial cells and
tumor cells controls. Understanding such interactions
clearly opens the potential for the development of novel
cancer treatments based on the inhibition of cancer
promoters (Labelle et al., 2001). As such, the
underlying mechanism by which coagulation factors
promote tumor cell growth, invasion, metastasis and
angiogenesis has recently become a hot topic in the
field of cancer research (Ma et al., 2011).
The confirmation that small daily doses of aspirin
reduce metastasis and help treatment of some cancers is a
most recent indicator of the role that platelets and
coagulation factors can play in cancer (Rothwell et al.,
2012). It is increasingly believed that blocking the chain
of events of the coagulation cascade upstream of its
activation process have a strong potential for limiting the
progression of tumors (Zacharski, 2011) and may
translate into improved therapy and patient survival.
Although, the beneficial effects of low molecular weight
heparins (LMWH) in cancer-related VTE prevention and
treatment is well established, their effect on survival in
cancer patients, remains controversial (Meyer et al.,
2011; Doormaal et al., 2011), suggesting that every
anticoagulation approach to restrain activation of
coagulation and platelets should be looked for.
III-Platelet role in cancer:
III-a Platelet count: By their capacity, upon activation,
to adhere to exposed sub-endothelium in a flow-
dependent manner, to aggregate and to facilitate
thrombin generation, platelets have long been
recognized as the primary hemostatic tool, with
deficiencies resulting in bleeding and up-regulation
favoring thrombosis. Yet, increasing evidence indicates
that platelets fulfill a much wider role in balancing
health and disease. Platelets are a source of active
metabolites and proteins, promote heterotypic cell
interactions and provide a biologically active surface,
together with a capacity to release cell-derived micro
particles that promote coagulation and protease
activation. Platelets also exert an active role in sepsis,
inflammation, tissue regeneration and control of

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132
infection (including promoting the innate immune
response) (Nurden, 2011).
Furthermore, observations have suggested that
platelets not only augment the growth of primary
tumors via angiogenesis but endow tumor cells physical
and mechanical support to evade the immune system
and, through induction of Epithelial-Mesenchymal-Like
Transition (EMT) of tumor cells, facilitating
extravasation to secondary organs, the basis of
metastatic disease. Many laboratory and animal studies
have identified specific targets for antiplatelet therapy
that may be advantageous as adjuncts to existing cancer
treatments (Jain et al., 2010).
The involvement of platelets and coagulation
factors in hematogenous tumor metastasis has long
been recognized. As a more direct evidence of platelet
involvement in the development of malignant tumors, a
relationship between elevated platelet count and
malignant tumors was reported as early as 1872 by
(Tranum and Haut, 1974). Ayhan et al. (2006),
demonstrated that higher preoperative platelet counts,
even if lying within the normal range (150.000-400.000
microl
-1
), may reflect poor prognostic factors such as
cervical involvement and high grade among patients
with endometrial carcinoma. These authors went even
further, questioning the necessity of radical
hysterectomy in patients with higher counts (Ayhan et
al., 2006). Similar observations were made in other
gynecological malignancies (Hernandez et al., 1992;
Zeimet et al., 1994) and in gastrointestinal tumors
(Ikeda et al., 2002; Shimada et al., 2004).
III-b Platelet activation markers: Platelets can be
activated by human and experimental tumor cells, a
process described in 1968 as “Tumor Cell-Induced
Platelet Aggregation» (TCIPA). It became apparent that
this aggregation correlates with the metastatic potential
of cancer cells in vivo (Karpatkin et al., 1988; Joseph,
1995; Al-Mondhiry, 1983). Compared with those in
complete remission, patients with active malignant
disease have elevated levels of beta-thromboglobulin
and platelet factor 4 (Al-Mondhiry, 1983) Circulating
activated platelets have also been evidenced in cancer
patients by detection of the platelet membrane antigens
CD62 (p-selecting) and CD63 (Wehmeier et al., 1991).
Tumor cells or membrane vesicles that have been shed
spontaneously from tumor cells can directly aggregate
platelets in vitro (Jamieson and Scipio, 1982) and can
induce platelet aggregation through the release of
proaggregatory mediators including adenosine
diphosphate, thrombin and a cathepsin-like cysteine
proteinase (Grignani and Jamieson, 1988).
Metastasis comprises multiple, consecutive steps.
Several cell adhesion molecules are involved in the
various stages of cancer metastasis (Huang et al.,
1997). CD 62P-derived from platelets can bind to a
variety of human cancers and human cancer-derived
cell lines, such as colon cancer, lung cancer including
small-cell lung cancer, breast cancer, malignant
melanoma, gastric cancer, neuroblastoma and adenoid
cystic carcinoma of the salivary gland. An increasing
body of in vivo experimental evidence indicates that P-
selection plays important roles in the growth and
metastasis of cancers (Chen and Geng, 2006). The
ligand molecules on cancer cells for P-selection,
however, remain unidentified. Several lines of evidence
suggest that the binding of human cancer cells, derived
from various organs and/or tissues, to P-selection may
be mediated by very different glycoprotein ligands
(Palumbo et al., 2005). Platelet depletion, or even an
inhibition of TCIPA, reliably diminishes metastasis,
seemingly without affecting the growth of established
tumors, in different in vivo models of experimental
pulmonary metastasis as well as in a murine model of
spontaneous metastasis (Palumbo et al., 2005).
Platelet/tumor cell/endothelial interactions have also
been reported helping in establishing metastatic lesions
(Rickles and Falanga, 2001).
III-c Platelet growth factors on immune cell
function, tumor progression and tethering: Platelets
and their byproducts, released upon platelet activation
through degranulation, appear to limit the ability of
Natural Killer (NK) cells to lyse tumor cells in vitro and
in vivo (Palumbo et al., 2005). Furthermore, platelet-
derived transforming growth factor-β (TGF-β) down-
regulates the activating immunoreceptor NKG2D on
NK cells (Kopp et al., 2009) and has been shown to
favor EMT in various cancer cell lines, thereby
potentially facilitating metastasis.
A number of growth factors supporting tumor
growth and possibly angiogenesis, such as Platelet-
Derived Growth Factor (PDGF), Vascular Endothelial
Growth Factor (VEGF) and angiopoetin-1, are released
by platelets, further interplaying and enhancing tumor
progression (Kepner and Lipton, 1981; Mohle et al.,
1997; Nierodzik and Karpatkin, 2006) and regulating
tumor vascular biology, preventing intralesional
hemorrhages (Noe et al., 2008; 2009). Furthermore,
some platelet byproducts/tumor cell receptor
interactions are associated with more tumor biological
aggressiveness. PDGFR-alpha, a receptor for PDGF,
expressed in invasive breast carcinomas is a good
example of this phenomenon (Oft et al., 1998).
Dendritic Cells (DCs) are key players in the
initiation of adaptive immune responses and are
currently exploited in immunotherapy for treatment of
cancer (Cruz et al., 2012). Platelets seem to secrete a
soluble DC-activating factor and are active elements of
the immune system that might play a role in balancing

Am. Med. J. 3 (2): 130-140, 2012
133
the ability of DCs to polarize T cell responses
(Cognasse et al., 2008).
Glycoprotein Ib-IX-V-complex (GPIb-IX-V) along
with GPVI on the surface of platelets are primarily
responsible for initial platelet adhesion and activation
by binding to their major legend, Von Willebrand
Factor (VWF) and collagen, respectively (Smyth et al.,
2009). Glycoprotein GPIbα and the A1 domain of VWF
immobilized on collagen or on the surface of activated
platelets are crucial for the initial tethering and rolling
of platelets at the site of vascular injury. Engagement of
GPIbα is required for downstream activation of the
integrin receptor and is thus an important initial step
in the cascade that can finally lead to firm thrombus
formation (Erpenbeck and Schon, 2010). Exceptionally,
some tumor cell lines, such as MCF7 cells, derived
from a human breast cancer, may express GPIbα
themselves (Oleksowicz et al., 1995). Inhibition of
GPIbα could enhance metastasis, an observation in
apparent contrast to most publications dealing with
platelets and metastasis. It is conceivable that blockade
of platelet GPIbα could result in an increased
availability of P-selectin for tumor cell-endothelial
interactions, thus supporting the attachment of tumor
cells to the vascular (Erpenbeck and Schon, 2010).
III-d Platelet integrins: Heterodimeric receptors of the
β1 and β3 integrin families mediate platelet adhesion
and aggregation in hemostasis and thrombosis. In
resting platelets, integrins are expressed in a low-
affinity state but they shift to a high-affinity state and
efficiently bind to their ligands in response to cellular
activation. The 2 interns considered to be most
important for platelet adhesion and aggregation are
integrins α
2
β
1
and α
II
bβ
3
(GPIIb/IIIa) (Nieswandt et al.,
2009). Although little is known about α
2
β
1
in platelet-
dependent cancer cell metastasis, this integrin receptor
appear to play a role for the adhesion of certain cancer
cell lines, like pancreatic tumors, to the extracellular
matrix (Hall et al., 2008). In contrast, the relation
between α
II
bβ
3
(GPIIb/IIIa) and metastasis of different
tumor cell lines has long been established rendering this
receptor an attractive target for anti-metastatic therapy
(Erpenbeck and Schon, 2010). Activation of platelet
GPIIb/IIIa seems to be necessary for the release of
angiogenic factors stored in platelet granules, such as
VEGF, crucial for tumor spreading, PDGF, TGF-β and
fibrinogen (Trikha et al., 1998; Amirkhosravi et al.,
1999). Many tumor cell lines express themselves the
same integrins that are normally found on platelets,
namely GPIb and αIIbβ3 (GPIIb/IIIa), adding to their
malignant potential (Trikha et al., 1998; Chen et al.,
1997). Therefore, it is not surprising to consider an
independent role for their ligand vWF in tumor
metastasis (Terraube et al., 2007).
III-e Adenosine diphosphate: Adenosine Diphosphate
(ADP) is a platelet agonist that causes platelet shape
change and aggregation as well as generation of
thromboxane A
2
, another platelet agonist, through its
effects on a family of purinergic receptors: P2Y1,
P2Y12 and P2X1 (Jianguo et al., 2002). Several tumor
cell lines possess the ability to generate ADP
themselves inducing a TCIPA (Boukerche et al., 1994).
IV Activation of Coagulation and cancer: The
prothrombotic state of cancer is driven by specific
oncogenic events. Activation of the coagulation cascade
appears integrally linked to the processes of tumor
growth, metastasis and angiogenesis (Tarek and
Khorana, 2009).
IV-a Tissue factor: Tissue Factor (TF) is best known
as the primary cellular initiator of blood coagulation.
After vessel injury, the TF: FVIIa complex activates the
coagulation protease cascade, which leads to fibrin
deposition and activation of platelets (Mackman, 2004).
In cancer-related thrombosis, the role of TF has
gathered the most attention (Tarek and Khorana, 2009).
This trans-membrane glycoprotein is expressed in a
variety of human cancers, induced by activation of
oncogenes or inactivation of tumor suppressor genes
(Yu et al., 2005). Over-expression of TF in tumor cells
or elevated TF levels in association with micro-particles
in the systemic circulation may contribute to systemic
hypercoagulability (Dvorak et al., 1981; Khorana et al.,
2007; 2008; Tesselaar et al., 2007; Uno et al., 2007). In
experimental models, cell lines often release TF-
positive Microparticles (MP) triggering thrombosis
(Wang et al., 2012). Translational research in humans,
conducted by Doormaal et al. (2012) on 43 cancer
patients without VTE at study entry and 22 healthy
volunteers, followed the markers of in vivo and MP-
dependent coagulation prospectively for six months and
for the development of VTE. They concluded that
although, median TF-mediated Xa-generation and
median VIIa-dependent fibrin generation test were
higher in the VTE group compared with the non-VTE
group. In this exploratory study the overall
hypercoagulable state in cancer patients was not
associated directly with the MP phospholipid-
dependent procoagulant activity. However, in the
patients who developed VTE within six months when
compared to those who did not, an increased MP
procoagulant activity was present already at baseline,
suggesting it could be used to predict VTE (Doormaal
et al., 2012).
Furthermore, TF may exert non-hemostatic roles in
the generation of coagulation proteases and subsequent

Am. Med. J. 3 (2): 130-140, 2012
134
activation of Protease Activated Receptors (PARs)
on vascular cells. This TF-dependent signaling
contributes to a variety of biological processes,
including inflammation, angiogenesis, metastasis and
cell migration (Tarek and Khorana, 2009).
Interestingly, inhibition of PAR1 or the presence of
specific polymorphism such as 506I/D are associated
with a better outcome in patients with breast cancer
(Eroglu et al., 2012).
Finally, TF pathway regulates mechanisms which
involve plasmin and matrix metallo-proteinases, both of
which seem to be critical in oral carcinogenesis
(Yapijakis et al., 2012).
IV-b Factor Xa and TF-FVIIa-FXa complex:
Coagulation factor zymogens activated upstream of
thrombin, including Factor Xa (FXa), may also exert
signalling via PARs and thus induce cellular effects
independent of thrombin generation (Krupiczojc et al.,
2008). The combination of FVIIa and FXa, but not
FVIIa alone, strongly induced migration of tumor cells
by a pathway that probably involves PAR2, but not
PAR1, activation. TF-FVIIa-mediated signaling in
human breast cancer cells occurs most efficiently by
formation of the TF-FVIIa-FXa complex (Jiang et al.,
2004). One of the physiological consequences of this
signaling pathway is enhanced cancer cell migration
mediated by mTOR pathway activation (Jiang et al.,
2008). Furthermore, the TF-FVIIa-FXa complex
prevents apoptosis in breast cancer cells by a thrombin-
independent pathway (Jiang et al., 2006). Quite
unexpectedly, FXa alone markedly diminished the
migration of different cancer cell lines of various
origins (breast, lung and colon cancer cells) and FXa
mediated inhibition of cancer cell migration was
specific, as it was inhibited by TAP (a specific FXa
inhibitor) but not by Hirudin (a specific thrombin
inhibitor) (Borensztajn et al., 2009). The role of
specific Xa inhibitors in the prevention of cancer
related thrombosis, remains however controversial
although initial results support further study of
apixaban, a specific oral FXa inhibitor, in phase III
trials to prevent VTE in cancer patients receiving
chemotherapy (Levine et al., 2012).
IV-c Thrombin: Thrombin, the key terminal enzyme
of coagulation, also promotes angiogenesis and
stimulates tumor-platelet adhesion, adhesion to
endothelium, tumor implantation, tumor cell growth
and metastasis. The thrombin receptor is expressed on
many tumor cell lines and on breast tumor biopsy
specimens (Ruf et al., 2010). In addition to the
mitogenic effects on fibroblast, smooth muscle cells
and endothelial cells, thrombin also exerts direct
effects on cancer cells (Green and Karpatkin, 2010). It
is also worth noting that thrombin is the key legend of
PAR firing inflammation and cell migration (Eroglu et
al., 2012). Furthermore, thrombin-induced Cathepsin
D, in term, contributes to the malignant phenotype by
inducing tumor cell migration, nodule growth,
metastasis and angiogenesis (Hu et al., 2008). The
activation of fibrinogen by thrombin and its cleavage
to fibrin monomers result in the rapid formation of
fibrin matrix. Furthermore, it is well documented that
fibrinogen and cross-linked fibrin reside inside the
tumor stroma (Yapijakis et al., 2012). Paradoxically,
thrombin-mediated thrombomodulin may act through
attenuation of the tumor-promoting properties of
thrombin, but it also may function as a cell-to-cell
adhesion molecule, independently of its anticoagulant
action (Yapijakis et al., 2012). Not surprisingly, in
xenographic tumour models, direct thrombin
inhibitors-like hirudin-have shown a significant
carcinostatic effect (Nowak et al., 2007). By virtue of
their anti-thrombin properties and beyond, heparin or
LMWH remain the cornerstone agents for the
treatment and prevention of cancer-related thrombosis
(Kahn et al., 2012).
Many studies alluded to the beneficial effects of
LMWH on survival in cancer patients and a systematic
review concluded that LMWH improves overall
survival in cancer patients, even in those with advanced
disease (Lazo-Langner et al., 2007). A recent study,
however, did not show a survival benefit of nadroparin
in patients with advanced prostate, lung, or pancreatic
cancer (Doormaal et al., 2011).
IV-d Fibrinogen and Fibrin: Fibrinogen is the final and
most important component of the coagulation cascade, as
well as a major determinant of blood viscosity and blood
flow and an important acute phase reactant.
Epidemiological studies increasingly suggests that
elevated plasma fibrinogen levels are associated with an
increased risk of cardiovascular disorders, including
Ischaemic Heart Disease (IHD), stroke and other
thromboembolisms (Meade et al., 1986; Wilhelmsen et
al., 1984). Hyperfibrinogenemia may be a predictor for
poor chemo-response and has a potential role as
independent prognostic factors in ovarian, rectal and
renal cell carcinoma patients. Moreover, it can be used as
a biomarker to predict therapeutic response (Qiu et al.,
2012; Xiao et al., 2011; Lu et al., 2011) or a risk
predictor for smoking-related cancers (Silva et al., 2010).
There is also evidence that fibrin deposition induced
by tumour cell-associated tissue factor and probably
platelets, protect tumor cells from a recognition by NK
cells contributing to enhancing metastasis.
IV-e Natural anticoagulants: Activated Protein C
(APC) and Protein C Inhibitor (PCI) are the major
components of the anticoagulant protein C pathway and
are the two proteins raising most interest for their

Am. Med. J. 3 (2): 130-140, 2012
135
potential role in regulating cancer. APC and PCI play
many roles not only in the regulation of hemostasis but
also in cell inflammation, proliferation, apoptosis,
tumor cell migration, invasion and metastasis. APC
promotes tumor cell invasion by EPCR-mediated and
PAR-1-mediated protease activity whereas PCI inhibits
tumor cell invasion in vitro by its protease inhibitory
activity and suppresses tumor cell growth, metastasis
and angiogenesis independent of its protease inhibitor
activity (Suzuki and Hayashi, 2007).
Abnormalities in Protein S seem to be rather
functional with reported dysregulation of S-
nitrosylation, a process that related to cancer
progression and dissemination (Wang, 2012).
Quantitation of protein S, seems however, non-specific
and redundant (Battistelli et al., 2005).
The role of Antithrombin (AT) is controversial as
early studies have reported an elevated level of AT in
patients with bladder and renal malignancy (Zietek et
al., 1997a; 1997b). Others have reported that their
cancer patients with localized prostate cancer had
significantly lower levels of AT III activity and higher
plasma D-dimer levels (Fidan et al., 2012).
Furthermore, others have advocated the use of low AT
and raised D-Dimer as prognostic markers for
gynecological malignancy (Koh et al., 2001; 2006). As
one would have expected, elevated Thrombin
Antithrombin Complex (TAT) observed in malignancy
correlated with its severity and was often associated
with abnormalities in the Thrombin Activatable
Fibrinolysis Inhibitor (TAFI) (Hong et al., 2010; Kaftan et
al., 2011). Further studies are deemed necessary to clarify
the possible relation between AT level and cancer.
Tissue factor pathway inhibitor, the physiological
inhibitor of TF, may also play a role in cancer. A pro-
apoptotic effect of TFPI has been found in breast
cancer cells in vitro, while corresponding
downregulation of endogenous TFPI resulted in
reduced apoptotic activity. Newer data suggest an
anti-metastatic effect of TFPI and suggest it can be a
novel therapeutic approach in cancer.
IV-f Fibrinolysis: Early studies have demonstrated
without doubt, the role of activated coagulation and
impaired fibrinolysis in patients with cancer (Laug et
al., 1975; Rocha et al., 1989; Zacharski et al., 1992).
There is now, however, good evidence that parts of the
fibrinolytic system, such as urokinase-type plasminogen
activator and its receptor (“uPAR”), can be used as
strong predictors of outcome and targets in several
types of cancer, specifically breast cancer (Korte, 2000;
Al-Hassan et al., 2012). Disseminated intravascular
coagulation with excessive fibrinolysis has been
described in the context of advanced prostatic
carcinomas (Hyman et al., 2011). Adjuvant
chemotherapy in cases of breast or prostatic carcinomas
further interferes with the fibrinolytic system favoring
thrombosis (Oberhoff et al., 2000; Varenhorst and
Risberg, 1981).
CONCLUSION
Applications for translational therapy of cancer:
Challenging issues and unresolved questions still need
to be addressed to understand the complexity existing
between coagulation factors and platelet components
and the different stages of cancer progression.
However, important findings have been obtained in the
last few years in the understanding of cancer-associated
thrombosis that can serve to understand the link
between coagulation and cancer. Such knowledge is
opening perspectives not only to better identify and
treat patients at risk of VTE, but also possible to design
new, possibly individualized therapy, to stop cancer
progression and metastasis. Much bench work and
clinical developments are still needed in the
comprehension of the intimate relationships existing
between activation of the coagulation system and
platelets and cancer progression and metastasis. The
role that coagulation and platelets play at the distinct
stages involved in cancer progression, in particular in
tumour cell protection and hematogenous metastasis,
needs major clarifications. Recent discoveries are
leading clinicians to consider new therapeutic
applications of anticoagulant therapies or new drugs
targeting specific platelet functions in cancer patients’
management. Possibility to use anticoagulants, either
already available or to be developed (LMWH, aspirin,
warfarin, cyclooxygenase inhibitors, P-selectin
inhibitor, integrin αIIbβ3 antagonists and others) in the
treatment of tumour progression and inhibition of
metastasis represent a promessing avenue of clinical
research development, already found effective in
animal models (Gay and Felding-Habermann, 2011).
Coagulation (TF, FXa, FVIIa, AT, fibrinogen,
thrombin, PC, PCa, TFPI) and platelet (P-selectin,
PDGF, TGF-β, VEGF, PF4) markers are clearly
associated, as causative agents or as markers, to cancer
development and evolution. Following their evolving
levels in patients can therefore also be considered as a
means to optimize treatment options and possibly they
can also serve as early biomarkers for dormant tumors.
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