338 © Schattauer 2010 Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Frequency, demographics and risk (according to tumour type or site)

of cancer-associated thrombosis among patients seen at outpatient
DVT clinics
Shankaranarayana Paneesha1; Aidan McManus2; Roopen Arya3; Nicholas Scriven4; Timothy Farren5; Tim Nokes6; Sue Bacon7;
Anthea Nieland8; Derek Cooper9; Harry Smith10; Denise O'Shaughnessy11; Peter Rose12; for the VERITY Investigators
1Consultant,Department of Haematology, Heart of England NHS Foundation Trust, Birmingham, UK; 2Director, MMRx Consulting, Cheam, Surrey, UK; 3Consultant, Department
of Haematology, King's College Hospital, London, UK; 4Consultant, Medical Assessment Unit, The Calderdale Royal Hospital, Halifax, UK; 5Clinical Scientist, Department
of Haematology, Barts and The London School of Medicine and Dentistry, London, UK; 6Consultant, Department of Haematology, Derriford Hospital, Plymouth, UK; 7Thrombosis
Nurse Specialist, Scarborough Hospital, Scarborough, UK; 8 Thrombosis Nurse Specialist, Northampton General Hospital NHS Trust, Northampton, UK; 9Statistical Consultant,
London, UK; 10Harry Smith, Medical Advisor, Sanofi Aventis UK*; 11Special Advisor, Blood Policy Unit, Department of Health, London, UK; 12Consultant, Department
of Haematology, Warwick Hospital, Warwick, UK

Summary
Venous thromboembolism (VTE) is a clinically important complication
for both hospitalised and ambulatory cancer patients. In the current
study, the frequency, demographics and risk (according to tumour site)
of VTE were examined among patients seen at outpatient DVT (deep-
vein thrombosis) clinics. Of 10,015 VTE cases, 1,361 were diagnosed
with cancer, for an overall rate of cancer-associated VTE of 13.6% in this
outpatient population. Patients with cancer-associated VTE were sig-
nificantly older than cancer-free VTE cases (66.4 ± 12.7 vs. 58.8 ± 18.5
years; p<0.0001). The frequency of cancer-associated VTE peaked ear-
lier among females than males, occurring in the sixth (137/639, 21.4%
vs. 98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs.
197/1096, 18%; p=0.036). VTE was described most frequently in com-
mon cancers – breast, prostate, colorectal and lung (56.1% of cases).
The risk of VTE varied widely across 17 cancer types. Calculating odds
ratios (OR) to assess the effect size of cancer type on VTE risk, the high-
est odds were observed for patients with pancreatic cancer (OR 9.65,
95% confidence interval [CI] (5.51–16.91). Tumours of the head and
neck had higher odds than previously reported (OR 8.24, 95% CI
5.06–13.42). Reduced risk estimates were observed for skin cancers
(melanoma and non-melanoma: OR 0.89, 95% CI 0.42–1.87; OR 0.74,
95% CI, 0.32–1.69, respectively). We conclude that outpatients have a
similar rate of cancer-associated VTE as VTE patient populations pre-
viously reported, that cancer-associated VTE occurs in an older age
group and earlier in females and that outpatients exhibit distinct tu-
mour site-specific risk from that described among hospitalised cancer
patients.
Keywords
Clinical studies, cancer, venous thrombosis

Correspondence to: Financial support:

Dr. Peter Rose The VERITY registry is funded by sanofi-aventis.
Consultant Haematologist, Department of Haematology
Warwick Hospital, Warwick, CV34 5BW, UK Received: June 24, 2009
Tel.: +44 1926 495321, ext. 4209 Accepted after major revision: October 26, 2009
E-mail: Peter.Rose@swh.nhs.uk Prepublished online: December 18, 2009
doi:10.1160/TH09-06-0397
* Current position: Medical Manager, Pfizer, Walton-On-The-Hill, Surrey, UK. Thromb Haemost 2010; 103: 338–343

Introduction
Venous thromboembolism (VTE) is a clinically relevant disease in
cancer patients (1), with recent studies suggesting it is becoming
more frequent (2). Large studies have shown that clinically appar-
ent VTE is associated with worse mortality in cancer patients than
non-cancer patients. In hospitalised cancer patients undergoing
potentially curative surgery, fatal pulmonary embolism (PE) de-
tected at autopsy was three-fold higher than in patients without
cancer undergoing surgery at the same sites (3). A Dutch cancer
registry that matched cancer patients with and without VTE
showed a 2.2-fold mortality increase in those with cancer-associ-
ated VTE (4). More recently, a study of ambulatory cancer patients
beginning chemotherapy showed that thromboembolism (includ-
ing arterial events) was a leading cause of death, accounting for up
to 9% of mortality (5).
The distinction between hospitalised cancer patients and those
patients receiving outpatient care is important when considering
thrombosis risk and prevention. The benefit of heparin-based
thromboprophylaxis has been proven in selected cancer surgery in-
patients (6), but this is not the case for cancer outpatients with meta-
static breast or lung cancer (7), or for those patients with intravenous
catheters (8), for whom clinical trials of low-molecular-weight hepa-
rin (LMWH) showed no benefit. These findings are reflected in cur-
rent guidelines that do not recommend thromboprophylaxis in
cancer outpatients (9, 10). This suggests that high-risk populations
have not been accurately identified and that a greater understanding
is required of cancer-associated thrombosis in outpatients to ident-

Thrombosis and Haemostasis 103.2/2010

 Paneesha et al. Cancer-associated VTE in outpatient DVT clinics 339

ify appropriately high-risk subgroups of cancer patients. In the cur-

rent study, we conducted an analysis to define the frequency, demo-
graphics and risk (according to tumour site) of cancer-associated
VTE among patients seen at outpatient DVT clinics.

Materials and methods

Patients

UK hospitals participating in the VEnous thromboembolism Reg-

IsTY (VERITY) prospectively enroll patients attending DVT out-
patient clinics. Details of the VERITY registry have been published
previously (11, 12). Data (demographic characteristics, medical
history, presenting symptoms, diagnosis, treatment practices in-
cluding location of treatment and follow-up data) are collected by
trained hospital staff in a standardised electronic case report form
and submitted to the electronic database. Patient data are anony-
Figure 1: Patients included in study.
mised. Centers enroll patients presenting with suspected VTE and
are requested to complete the case report form irrespective of
whether the final diagnosis of VTE is positive. A variety of algo- was considered statistically significant. All analyses were con-
rithms, mainly based on D-dimer measurement and pre-test prob- ducted using a commercial software package (SPSS version 16;
ability, are used to exclude VTE. Confirmatory, objective testing is SPSS Inc., Chicago, IL, USA).
undertaken according to local protocols, usually including ultra-
sonography or venography for suspected DVT and pulmonary an-
giography, lung scintigraphy or helical computed tomography
scan for suspected PE (12). Results
This analysis included patients who presented with suspected
VTE for whom the VTE diagnosis was recorded, together with the Patients
presence or absence of a cancer diagnosis. Data were validated to
eliminate, as far as possible, data entry problems. Cancer is defined Between February 2005 and March 2008, 49,044 patient entries
in the database as current or having received treatment for cancer in were made online in the VERITY registry by 43 hospitals in the UK.
the last six months. On the cancer screen, 17 specific cancer types are VTE status (confirmed or excluded) and cancer status (malignan-
listed [bone/sarcoma, breast, central nervous system (CNS), colorec- cy or no malignancy) was known for 41,367 patient entries. Data
tal, endocrine, gynecologic, head/neck, leukemia, lung, lymphoma, validation excluded 166 entries, for reasons of no hospital name
melanoma, myeloma, non-melanoma, pancreas, prostate, urologi- specified (n=86), female prostate cancer (n=11) and others
cal, upper gastrointestinal (GI)] with other. No record is made of (n=69). In total, 41,201 patient entries from 39,618 individual pa-
metastatic disease, but patients with multiple cancer sites are rec- tients were included in this analysis (씰Fig. 1).
orded; no histological description, tumour grade or stage are rec-
orded. We included patients who had a diagnosis of cancer after the
initial presentation for VTE in the analyses.
VTE and cancer

VTE was diagnosed in 10,015 (25.3%) of the 39,618 patients in the

Statistical analysis
The Chi2 test was used to analyse the difference in categorical vari-
ables. The mean age at consultation was compared between groups
using the independent samples t-test and one-way analysis of vari-
ance (ANOVA); the Games-Howell post-hoc test was used for pair-
wise comparisons. Odds ratios (ORs) and corresponding 95%
confidence intervals (CIs) were calculated for individual cancer
types. Age- and sex-matched comparisons were made using a
matched dataset derived from the main dataset. A p-value <0.05
registry and cancer was diagnosed in 2,804 patients. Cancer type
was specified in 2,308 (82.3%) cancer cases; in 207 cases, cancer
type was recorded as “other” (i.e. not one of the 17 cancer types
listed) and in 298 cases, no record of cancer type was made. In 165
cases, more than one cancer site was reported. Among VTE cases,
13.6% (1,361/10,015) carried a diagnosis of cancer (씰Table 1).
There were 1,164 DVT, 22 cases of DVT and PE, 116 cases of PE and
59 cases designated as VTE.
The diagnosis of cancer was more frequent in VTE cases than in
VTE-negative patients: 13.6% vs. 4.9% (1,443/29,603), OR 3.07

© Schattauer 2010 Thrombosis and Haemostasis 103.2/2010

340 Paneesha et al. Cancer-associated VTE in outpatient DVT clinics

Table 1: Cancer and VTE status for patients included in the study. were significantly older (66.43 ± 12.7 vs. 58.85 ± 18.5 years;
p<0.0001).
Cancer Total
There were marked differences in age distribution; cancer-as-
No Yes sociated VTE was less prevalent in the first five decades of life, but
No VTE 28,160 1443 29,603 markedly more prevalent in the seventh and eighth decades (씰Fig.
VTE 8654 1361 10,015 2). Among VTE patients, the proportion of those with cancer in-
Total 36,814 2804 39,618 creased with increasing age, with gender-specific differences
(씰Fig. 3). The peak incidence of cancer-associated VTE occurred
earlier among females than males, in the sixth (137/639, 21.4% vs.
98/851, 11.3%; p<0.001) and seventh decades (213/980, 21.7% vs.
Table 2: Age, cancer and VTE. 197/1096, 18%; p=0.036), and was more frequent in males than fe-
males in the eighth (198/934, 21.2% vs. 183/1054, 17.4%; p=0.035)
All VTE
and ninth decades (65/350, 18.6% vs. 82/708, 11.6%; p=0.001).
All Non-cancer Cancer Cancer was uncommon in VTE patients younger than 31 years
Valid 39,609 10,008 8647 1361 (19/745; 2.6%).
Missing 9 7 7 0
Mean, years 60.38 59.88 58.85 66.43
Median, years 63.00 62.00 61.00 68.00
Cancer sites in VTE patients
Standard deviation, 18.23 18.05 18.54 12.70
years
Four common cancers (breast, prostate, colorectal and lung) ac-
Range, years 4–102 4–102 4–102 22–96
counted for 56.1% (724/1290) of the VTE cases (for whom cancer
site was specified). Certain tumour sites were more common in
VTE cases than non-VTE cases, including CNS, pancreas, upper GI
(95% CI 2.84–3.31; p<0.001). VTE was more frequent in patients and head/neck (씰Fig. 4).
with cancer (48.5%, 1,361/2,804) than those without cancer
(23.5%, 8654/36814; p<0.001).
Effect size of cancer type on VTE risk

Age and cancer-associated thrombosis The ORs and adjusted ORs for the association of specific cancers
with VTE are presented in 씰Table 3. The ORs of the four most
Age data are presented in 씰Table 2. Comparing non-cancer common cancers ranged from 1.94 (95% CI 1.57 – 2.39) for pros-
VTE cases with cancer-associated VTE cases, patients with cancer tate cancer to 4.01 (95% CI 3.26–5.32) for lung cancer. The highest

Figure 2: Age distribution in all VTE cases

and cases with cancer-associated VTE.

Thrombosis and Haemostasis 103.2/2010 © Schattauer 2010


Figure 3: Percentage of VTE patients with cancer within each age
decade by gender.
ORs for VTE [both adjusted (9.65, 95% CI 5.51–16.91) and unad-
justed (16.75, 95% CI 5.22–53.71)] were found in patients with
pancreatic cancer. Tumours of the head and neck had high odds
(OR 8.24, 95% CI 5.06–13.42). Reduced risk estimates were ob-
Figure 4: Distribution of VTE by cancer site.
© Schattauer 2010
Paneesha et al. Cancer-associated VTE in outpatient DVT clinics 341
served for skin cancers (melanoma and non-melanoma: OR 0.89,
95% CI 0.42–1.87; OR 0.74, 95% CI, 0.32–1.69, respectively). The
OR for VTE in patients with more than one cancer site was 3.46
(95% CI 2.67–4.48).
Discussion
This analysis of more than 10,000 patients with VTE in an out-
patient treatment setting found that one in seven had a diagnosis of
cancer. This is similar to the overall prevalence of cancer-associ-
ated thrombosis reported in the literature, which is described as
approximately 15% (1). This is despite the selected population of
cancer patients treated in an outpatient setting. Indeed, a recent
prospective clinical trial confirmed that cancer was the most com-
mon reason cited for in-hospital treatment of VTE (13). In our
study, cancer was three times more common in VTE cases than in
non-VTE cases, which is low in comparison with previous findings
(14, 15) but reflects the selected nature of the registry population,
in which patients with suspected VTE who subsequently had that
diagnosis excluded would be expected to have an over-represen-
tation of thrombosis-related risk factors such as cancer.
We found that cancer-associated VTE was most prevalent in the
seventh and eighth decades of life, with peaks occurring signifi-
cantly earlier in females than males reflecting, we suspect, the ear-
Thrombosis and Haemostasis 103.2/2010
342 Paneesha et al. Cancer-associated VTE in outpatient DVT clinics

Table 3: Odds ratios and adjusted odds ratios for VTE for specific relative risk of 0.29, and in the latter, a stage-adjusted OR of 1.0 was
cancer types or tumour sites. reported. In our analysis, head and neck cancers had the second
highest OR of 8.24, which is very similar to the risk experienced by
Cancer type OR 95% CI Adjusted OR 95% CI
patients with pancreatic cancer. This extreme difference in risk of
Pancreas 9.65 5.51–16.91 16.75 5.22–53.71
VTE we found for head/neck cancer outpatients is hard to explain,
Head/neck 8.24 5.06–13.42 7.54 3.60–15.78 but it is conceivable that inpatients have a markedly different risk
CNS 7.19 2.98–17.34 5.34 1.56–18.33 profile for VTE. However, for the comparison with the Chemo-
Upper GI 6.41 3.99–10.31 4.02 2.19–7.38 therapy Study Group Registry that enrolled outpatients, we feel
Endocrine 4.93 1.79–13.57 10.01 1.28–78.20 that our finding is more likely to be accurate given the large
Lung 4.17 3.26–5.32 3.87 2.73–5.49
number of cases with cancer-associated VTE (n=1,361) and head/
neck associated VTE (n=61) reported here and the small numbers
Colorectal 4.01 3.23–4.97 4.04 2.94–5.55
of VTE cases reported overall in the Chemotherapy Study Group
Multiple sites 3.46 2.67–4.48 3.05 2.14–4.35 Registry (n=60). Again, we suggest that these findings should con-
Myeloma 3.33 2.07–5.37 3.01 1.52–5.95 tribute to study design for the development of risk assessment
Bone/sarcoma 3.30 2.09–5.22 1.90 1.11–3.27 models for cancer outpatient VTE prevention.
Gynaecologic 3.05 2.38–3.91 3.74 2.56–5.47 Ovarian cancer was previously identified as conferring high risk
Urology 2.78 2.06–3.73 2.72 1.80–4.12 for VTE (21), but our specified cancer list used a more generalised
term (gynecologic cancer), which does not allow us to distinguish
Breast 2.52 2.11–3.01 2.94 2.27–3.82
between different cancer types in this grouping and may explain
Prostate 1.94 1.57–2.39 1.48 1.14–1.92 the relatively low OR found in our analysis. We found reduced risk
Lymphoma 1.92 1.32–2.78 2.00 1.19–3.39 estimates for skin cancers (melanoma and non-melanoma: OR
Leukemia 1.84 1.09–3.10 1.77 0.90–3.50 0.89, 95% CI 0.42–1.87; OR 0.74, 95% CI, 0.32–1.69, respectively).
Non-melanoma 0.89 0.42–1.87 1.00 0.40–2.52 These findings are in keeping with the annual incidence rates of
Melanoma 0.74 0.32–1.69 0.78 0.29–2.09 first time VTE in California residents in Olmsted County, with the
lowest cumulative VTE incidence reported for melanoma (21).
Other 3.44 2.62–4.53 3.79 2.51–5.71
Our data are not sufficiently detailed to provide further insight
Unspecified 1.55 1.21–1.97 2.03 1.44–2.86
into the role of metastatic disease or cancer stage and grade in VTE
VTE , venous thromboembolism; OR, odds ratio; CI, confidence interval; CNS, risk. Nonetheless, an OR of 3.46 for patients with more than one
central nervous system; GI, gastrointestinal. cancer site recorded is in keeping with the elevated risk of VTE
known to be associated with metastatic disease (2). Furthermore,
our data were not sufficiently detailed to allow us to determine the
lier peak seen in breast cancer than prostate cancer in the general impact of tumour- or stage-specific chemotherapy regimens, cen-
population. As far as we are aware, this is the first analysis of tral venous catheter placement or the timing of surgery on VTE
cancer-associated VTE by age and gender in the setting of out- risk and we did not review the prophylaxis history. To address these
patient care. Cancer patients with VTE were significantly older limitations of the registry, we have initiated further data collection
than non-cancer patients and our findings are almost identical to with a revised CRF for cancer patients to include metastatic disease
the MASTER Registry, which described an 8.1-year difference in fields and treatment history with the hope of offering more pre-
mean ages (16). On the basis of these findings, we suggest that age cise, tumour-specific VTE risk profiles.
and sex should be included as potential predictive variables when The ORs in this study were calculated by comparing the incidence
developing patient-specific risk assessment models for VTE pre- of cancer in the VTE sample with the incidence in the non-VTE
vention in cancer outpatients. sample. A more appropriate denominator is the population-based
The most common cancer types found in VTE outpatients were incidence of each cancer type, but such data on ambulant, non-VTE
breast, prostate, lung and colorectal, mirroring previous findings cases are not available. Thus, our denominator is a selected group
and reflecting the high prevalence of these cancers in the general and has the limitation of potentially introducing a referral bias. We
population (17). Among patients with cancer, our analysis showed would expect the ORs we calculated for VTE to be an underesti-
that those with pancreatic, head and neck, CNS and upper GI mation compared to the general population. In an attempt to adjust
cancers had the highest incidence of VTE. Our outpatient findings for this, we calculated ORs in an age- and sex-matched cohort. The
are largely consistent with previous reports, which describe high adjusted ORs were broadly similar, but were markedly increased for
risk associated with pancreatic, brain and gastric cancer (18), but pancreatic cancer and in particular for endocrine tumours, with re-
differ for head and neck cancers. Head and neck cancers have been duced ORs for upper GI and CNS tumours. This indicates that pan-
shown to be at the lowest risk of thrombosis, both in hospitalised creatic and endocrine tumours are markedly more thrombogenic
patients with a discharge diagnosis of VTE in the Medicare Pro- when age- and sex-matched cohorts are compared.
vider Analysis and Review Record database (19) and in outpatients Registry data should not be considered as robust as clinical trial
enrolled in the Awareness of Neutropenia in Chemotherapy Study data, and in VERITY there is no requirement to enroll consecutive
Group Registry (20). In the former, head and neck patients had a cases or to complete all data fields. This introduces the possibility of

Thrombosis and Haemostasis 103.2/2010 © Schattauer 2010


What is known about this topic?
● Venous thromboembolism (VTE) is a clinically relevant disease in
cancer patients.
● In patients with cancer-associated thrombosis, there are few data
describing the relationships among age, sex and cancer type.
● There is interest in defining outpatient-specific VTE risk.
What does this paper add?
● Patients attending outpatient DVT clinics have a similar rate of
cancer-associated VTE as VTE patient populations previously re-
ported.
● Cancer-associated VTE has distinct age- and sex-specific differ-
ences from the overall outpatient VTE group.
● We confirm previous reports of marked differences in tumour-spe-
cific VTE risk, and our data show that outpatients exhibit distinct
tumour site-specific risk from that described among hospitalised
cancer patients, in particular for patients with head/neck cancers
who are at higher risk than previously reported.
patient selection bias, with the least complicated patients with fewer
fields to complete potentially favored for entry into the database.
Data validation was performed to eliminate obvious data entry
problems but although the coding of the primary endpoint (diag-
nosis of VTE) was not subject to further validation, for example, by
confirming the diagnosis in the patient’s notes, we believe these diag-
noses are robust and will have been confirmed locally by imaging.
Our data are distinct from other population-based studies in which
the diagnosis of VTE is based on disease coding and which could be
considered less reliable. A limitation of this study is the lack of a pre-
cise definition of what constitutes an outpatient. The cancer patients
enrolled had contact with the outpatient clinic and were recorded in
the registry, but they may have been largely hospitalised during their
care and only briefly used the outpatient service.
Identification of ambulatory cancer patients most at risk of
VTE has the potential to improve patient outcome by reducing
death and morbidity through effective prophylaxis provision. The
framework to do this accurately must include tumour-specific pa-
rameters, patient-specific factors and account for risk factor inter-
actions. Interpretation of our findings in this context is limited by
our lack of data on the timing and type of therapeutic intervention
in these cancer patients. Nonetheless, our findings, particularly the
estimation of tumour-specific risk, will contribute to the design of
studies to identify patient groups that require VTE prevention.
Acknowledgements
The VERITY Steering Committee thanks the investigators for col-
lecting the data. Editorial assistance was provided by Dr. Lucy Hyatt.
© Schattauer 2010
Paneesha et al. Cancer-associated VTE in outpatient DVT clinics 343
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