Upper limb deep vein thrombosis: update on risk ... - Cancer Therapy

Cancer Therapy Vol 5, page 391
Cancer Therapy Vol 5, 391-394, 2007
<strong>Upper</strong> <strong>limb</strong> <strong>deep</strong> <strong>vein</strong> <strong>thrombosis</strong>: <strong>update</strong> on risk
factors in oncological patients
Review Article
Pierpaolo Di Micco 1, *, Rosanna Di Fiore 2 , Sandro Quaranta 2 , Giuseppe V.
Viggiano 3 , Ilaria J. Romano 3 , Alferio Niglio 3 , Andrea Fontanella 1 , Bruno De
Simone 1 , Antonella Angiolillo 4 , Giuseppe Castaldo 2
1 Internal Medicine Division, Buon Consiglio Fatebenefratelli Hospital of Naples, Naples, Italy
2 Department of Biochemistry and Medical Biotechnology, University of Naples “Federico II” and CEINGE-Advanced
Biotechnologies, Naples, Italy
3 Internal Medicine, Second University of Naples, Naples, Italy
4 School of Science, University of Molise, Isernia, Italy
__________________________________________________________________________________
*Correspondence: Pierpaolo Di Micco, MD, Internal Medicine Division, Buon Consiglio Fatebenefratelli, Hospital of Naples, Naples,
Italy, Phone: +39-33-98078146; Fax: +39-81-5468290; Email: pdimicco@libero.it
Key words: <strong>Upper</strong> <strong>limb</strong> <strong>deep</strong> <strong>vein</strong> <strong>thrombosis</strong>, Chemotherapy, Cancer acquired thrombophilia, Oncological surgery, Central venous
catheters, Concomitant illness, Inherited thrombophilia, UEDVT
Abbreviations: cancer procoagulants (CP); central nervous system (CNS); Central venous catheters (CVC); <strong>deep</strong> <strong>vein</strong> <strong>thrombosis</strong>
(DVT); Interleukin 1!, (IL-1!); Lower extremities <strong>deep</strong> venous <strong>thrombosis</strong> (LEDVT); port-a-cath (PaC); pulmonary embolism (PE);
pulmonary embolism (PE); tissue factors (TF); Tumor Necrosis Factor ", (TNF"); upper extremities <strong>deep</strong> venous <strong>thrombosis</strong> (UEDVT);
Venous thromboembolism (VTE)
Received: 1 October 2007; Revised: 27 October 2007
Accepted: 29 October 2007; electronically published: November 2007
Summary
Venous thromboembolism (VTE) is a multifactorial disease that may appear as <strong>deep</strong> <strong>vein</strong> <strong>thrombosis</strong> (DVT) of the
lower or upper <strong>limb</strong> and\or pulmonary embolism (PE). Venous thromboembolism is associated with several
inherited and\or acquired risk factors, cancer being the most common acquired thrombotic risk factor. Lower
extremities <strong>deep</strong> venous <strong>thrombosis</strong> (LEDVT) is more common than upper extremities <strong>deep</strong> venous <strong>thrombosis</strong>
(UEDVT), but cancer patients have an increased incidence of UEDVT due to additional risk factors such as central
venous catheters, chemotherapy, radiotherapy or the presence of bulky malignancies that induce prolonged
compression of <strong>vein</strong>s hence venous stasis. This review is focused on the analysis of inherited and acquired risk
factors for UEDVT in oncological patients.
I. Introduction
Venous thromboembolism (VTE) is a multifactorial
disease which may appear as <strong>deep</strong> venous <strong>thrombosis</strong> of
lower extremities (LEDVT) or more rarely of the upper
extremities (UEDVT) with possible life-threatening
complications such as pulmonary embolism (PE) ( Di
Micco et al, 2006). Risk factors for VTE may include an
inherited thrombotic predisposition and acquired trigger
factors (Martinelli, 2001).
UEDVTs account for approximately 4% of all VTE
events, and its incidence has increased in the last years
when compared to data from past decades (Monreal et al,
2006). The increase recorded may also be due to the
development of more accurate diagnostic supports, or
methods, such as vascular ultrasonography with color-
Doppler flow. There is a strong relationship between
cancer and VTE, in particular LEDVT (Piccioli et al,
2004), while other types of thrombotic events (e.g. arterial
<strong>thrombosis</strong> or disseminated intravascular coagulation) less
frequently appear as a complication of neoplasia (Brenner,
2001; Levi, 2001).
Cancer per se, is the most relevant acquired
thrombotic risk factor of VTE, because of its myriad of
prothrombotic molecules released by neoplastic cells
(Falanga, 2001). Bulky malignancies, which cause venous
compression, may also induce a prolonged venous stasis
(Brenner, 2001). Furthermore, chemotherapy can lead to
thrombotic events due to venous vessel irritation
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(Goodnought et al, 1984; Obheroff et al, 1998; Falanga,
2001). Central venous catheters (CVC) or port-a-cath
(PaC), which are placed to facilitate chemotherapy or
parenteral nutrition are known thrombotic trigger factors,
particularly for UEDVT (Di Micco et al, 2006; Monreal et
al, 2006).
Other potential risk factors for UEDVT during
malignancy, e.g., chronic hearth failure, chronic
obstructive pulmonary disease and haematopoietic colony
stimulating factors are currently under study (Haas, 2002;
Di Micco et al, 2006). Similarly, a series of genetic
potential prothrombotic factors are known, but their role in
pathogenesis of VTE in oncological patients is still under
discussion (Martinelli, 2001; Di Micco et al, 2004). Of
course, the identification of subjects with an inherited
thrombophilic genotype is mandatory, since they may
benefit from pharmacological thromboprophylaxis for
primary prevention of UEDVT.
The objective of this review is to discuss the risk
factors for UEDVT in cancer patients, and the possible
strategies to prevent the aforementioned complications.
II. Type of cancer
Initially described by Trousseau, several studies have
focused on the association between cancer and <strong>thrombosis</strong>
(Trousseau, 1865), and more specifically on the types of
cancer more frequently associated to vascular
complications (Levitan et al, 1999). Levitan and
colleagues, in fact, identified in 1999 a higher risk for
DVT in patients bearing ovarian cancer and cancer related
to the central nervous system (CNS). Bulky malignancies
are also frequently associated to VTE, because of
prolonged venous compression on the venous system,
which in turn induces venous stasis and hypercoagulable
state (Cyrkowicz, 2002; Di Micco et al, 2006). We
previously reported that haematological malignancies,
frequently associated to bulky compression on
mediastinum, can additionally induce prolonged
compression on the venous axis of the upper <strong>limb</strong>, hence
increasing the risk of venous <strong>thrombosis</strong> (Di Micco et al,
2004); ovarian cancer may also appear as a bulky
malignancy, whereby venous compression and venous
stasis increase the risk of <strong>thrombosis</strong> (Cyrkowicz, 2002).
III. Cancer acquired thrombophilia
The high occurrence rate of VTE in neoplastic
patients is mainly due to prothrombotic molecules released
from malignant cells, such as tissue factors (TF) or cancer
procoagulants (CP). Cancer cells may either express and
release TF themselves, (Falanga, 2001) or via stimulation
of monocytes, macrophages or endothelial cells. This
occurrence is mediated by a cytokine network, which is
related to cancer growth (Falanga, 2001). Interleukin 1!
(IL-1!) and Tumor Necrosis Factor " (TNF") are the
most well known cytokines involved in cancer-induced
thrombophilia (Falanga, 2001; Di Micco et al, 2006). The
typical effect of procoagulant molecules in patients
bearing neoplasia, is a subclinical hypercoagulable state
that may be detected by screening for biochemical
markers, such as D-dimer (Gouin-Thibault et al, 2001),
prothrombin fragment 1+2 (Gouin-Thibault et al, 2001)
and thrombin-antithrombin complexes (Gouin-Thibault et
al, 2001). The subclinical hypercoagulable state may lead
to relevant clinical thrombotic events (Di Micco and
D’Uva, 2003).
IV. UEDVT and malignancy
In addition to the production of procoagulant
molecules, other thrombotic risk factors may also be
involved in the pathogenesis of UEDVT in neoplastic
patients. These include: surgery, concomitant medical
illness, prolonged immobility, cancer therapies and the
presence of CVC\PaC (Di Micco et al, 2006). The
placement of CVC or PaC is usually performed on the
venous axis of the upper <strong>limb</strong>s (i.e. brachial <strong>vein</strong>, axillar
<strong>vein</strong>, subclavian <strong>vein</strong> or jugular <strong>vein</strong>). In these patients, we
may distinguish a full axis UEDVT (i.e. involving
brachial-axillar-subclavian axis with or without
involvement of internal jugular <strong>vein</strong>) or a selected
UEDVT (i.e., limited to a specific venous district) (Di
Micco and D’Uva, 2003). However, DVT localised to
subclavian or jugular <strong>vein</strong>s, is more frequently followed
by pulmonary embolism (Khorana et al, 2005).
V. Chemotherapy and other
treatments
VTE, and in particular UEDVT, are more frequent in
neoplastic patients undertaking ongoing chemotherapy;
such complications mainly occur during prolonged
treatment and in the presence of a CVC\PaC, particularly
in breast cancer patients and in cases of haematological
malignancies (Monreal et al, 2006). However, an
increased incidence of all forms of VTE has been
recorded, independent of CVC, in patients undergoing
chemotherapy since 1980 (9-10); this mainly occurs in
advanced stages of cancer (i.e. when metastasis occurs).
The prothrombotic role of chemotherapy has been studied
with regard to the chemotherapeutic regimen and the
specific drugs that more frequently cause VTE. A specific
prothrombotic action has been associated to the CMF
regimen (Koch et al, 1997) and thalidomide (Jorgensen et
al, 1993). Growth colony stimulating factors used during
chemotherapy-induced neutropenia, may also exert
prothrombotic activity, but the mechanism is still under
discussion (Rahr and Sorensen, 1992).
VI. Oncological surgery
Surgical procedures are a leading risk factor for VTE
(Martinelli, 2001). The association between major surgery
and VTE is known for a long time, and is usually related
to the post-surgical immobility, a further thrombotic risk
factor for oncological patients (Di Micco et al, 2006).
However, oncological surgery is associated to a higher risk
of thrombotic events as compared to non-oncological
surgery (Rahr and Sorensen, 1992; Kearon et al, 1998;
Martinelli et al, 2004), and a recent multicentric study
underlined an increased incidence of UEDVT in
oncological patients with recent surgery, in particular if
they carried a CVC (Monreal et al, 20063).
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VII. Central venous catheters and
UEDVT
Central venous catheterisation is a well-established
procedure in patients affected by malignancy to simplify
chemotherapy, blood transfusion, parenteral nutrition and
other therapies. We distinguish CVC, placed in central
venous line (e.g. subclavian or internal jugular <strong>vein</strong>) or
PaC, placed usually in another <strong>deep</strong> venous access of the
upper extremity. Since these kind of venous
catheterisation has been adapted in the daily clinical
management of oncological patients, an increased number
of complications has been pointed out, in particular <strong>deep</strong>
venous <strong>thrombosis</strong> of upper extremities and\or infections
(Rodeghiero and Elice, 2003; Monreal et al, 2006).
Two types of catheter-related <strong>thrombosis</strong> of upper
extremities may occur in these patients: a sleeve
<strong>thrombosis</strong> on the outside of the CVC or a vascular
<strong>thrombosis</strong> in which the <strong>vein</strong> is involved by the thrombotic
complication previously started on the CVC\PaC surface
(Rodeghiero and Elice, 2003).
A specific and fast diagnosis is required by
ultrasound scan with or without colour-Doppler flow,
followed by a careful clinical surveillance and follow-up
when an UEDVT is present, as several studies have
reported a frequent association between UEDVT and
pulmonary embolism, and in particular fatal pulmonary
embolism (Khorana et al, 2005). Although ultrasound scan
of venous axes of upper <strong>limb</strong> associated with compression
ultrasonogophy and\or colour Doppler flow examination is
the most accurate way to diagnosis an UEDVT according
to the international guidelines (i.e. relevant sensitivity and
specifity) (Kearon et al, 1998), in some cases venography
might be needed to confirm the presence of UEDVT.
VIII. Concomitant illness
Several patients affected by malignancy may bear
further medical illness which increase the risk for VTE.
All conditions inducing prolonged bedrest (i.e. chronic
obstructive pulmonary disease, chronic heart failure or
neurological disease) increase the risk to develop a
thrombotic event (Haas, 2002; Di Micco et al, 2006).
IX. Inherited thrombophilia and
UEDVT
Several studies analysing thrombotic risk factors in
patients affected by UEDVT showed an increased
incidence of inherited thrombophilia (Martinelli et al,
2004). Furthermore, inherited thrombophilia seems to be
also associated with an increased rate of recurrence for
UEDVT patients (30). On the other hand, the role of
inherited thrombophilia in patients suffering of VTE
during malignancy has so far been poorly investigated, and
is still under discussion. Thus, we may suppose a role for
inherited thrombophilia in the pathophysiology of UEDVT
during malignancy, although larger randomised trials are
required to confirm this hypothesis. Our preliminary study
focused on patients with UEDVT bearing haematological
malignancies seems to confirm the association between
inherited thrombophilia and UEDVT and haematological
malignancies (Di Micco et al, 2004). In our study, an
increased incidence of inherited thrombophilic conditions
such as factor V Leiden gene variants, prothrombin
A2021G gene variants, or mehtylenetetrahydrofolate
C677T gene variants, have been showed in haematological
patients affected also by UEDVT. On this clinical setting,
the knowledge of a prothrombotic state of such patient
with malignancy may be relevant, and might permit to
perform a specific thromboprophylaxis in order to avoid
VTE which represents one of the most common cause of
death in oncological patients.
X. Conclusions
In conclusion, VTE appears during malignancy as
LEDVT and\or UEDVT. Although, LEDVT is the most
frequent form of VTE during malignancy, the incidence of
UEDVT has been increasing in these last decades due to
more accurate diagnostic tools and to a better knowledge
of UEDVT risk factors and particularly surgery and
CVC\PaC. Moreover, bulky lesions seem to be the most
common diseases associated with UEDVT, due to the
induced prolonged venous compression and stasis and the
cancer-acquired thrombophilia; however UEDVT are
frequently associated to breast and lung cancer or
haematological malignancies. However, recent
multicentric studies are focused also to reveal further
underestimated thrombotic risk factor such as concomitant
medical illness, chemotherapy and\or presence of further
molecular prothrombotic condition (e.g. inherited
thrombophilia). A careful knowledge of inherited and
acquired thrombotic risk factors in oncological patients
may be relevant for daily clinical practice in order to
improve primary or secondary thromboprophylaxis of
VTE in oncology.
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