guideline
Guideline on aspects of cancer-related venous thrombosis
Henry G. Watson,1 David M. Keeling,2 Mike Laffan,3 Robert Campbell Tait,4 and Mike Makris5,6 on behalf of the British
Committee for Standards in Haematology
1
Department of Haematology, Aberdeen Royal Infirmary, Aberdeen, 2Oxford Haemophilia & Thrombosis Centre, Churchill Hospital,
Oxford, 3Centre for Haematology, Imperial College, Hammersmith Hospital, London, 4Department of Haematology, Glasgow Royal
Infirmary, Glasgow, 5Sheffield Haemophilia and Thrombosis Centre, and 6Department of Cardiovascular Science, University of
Sheffield, Sheffield, UK
Summary
The guideline was drafted by a writing group identified by the
Haemostasis and Thrombosis Task Force of the British Com-
mittee for Standards in Haematology (BCSH). All the authors
are consultants in haematology in the UK. A search was per-
formed of PubMed and Embase using the term ‘cancer’ com-
bined with ‘thrombosis’, ‘treatment’, ‘prophylaxis’ and ‘clinical
presentation’. The search covered articles published up until
December 2014. Only human studies were included and arti-
cles not written in English were excluded. References in recent
reviews were also examined. The writing group produced the
draft guideline, which was subsequently revised by consensus
by members of the Haemostasis and Thrombosis Task Force of
the BCSH and the BCSH executive. The guideline was then
reviewed by the sounding board of the British Society for Hae-
matology (BSH). This comprises 50 or more members of the
BSH who have reviewed the guidance and commented on
the content and application to the UK setting. The ‘GRADE’
system was used to quote levels and grades of evidence, details
of which can be found at: http://www.bcshguidelines.com/
BCSH_PROCESS/EVIDENCE_LEVELS_AND_GRADES_OF_
RECOMMENDATION/43_GRADE.html. The objective of this
guideline is to provide healthcare professionals with clear guid-
ance on the prevention and management of venous thrombo-
embolism (VTE) in patients with cancer and to advise on an
approach to screening for cancer in patients with unprovoked
VTE in whom cancer was not initially suspected based on clin-
ical grounds.
Keywords: cancer, clinical aspects, venous thrombosis, anti-
coagulation.
The association between cancer and thrombosis is well estab-
lished. There are several mechanisms that may explain why
cancer increases the propensity to develop venous thrombo-
Correspondence: BCSH secretary, British Society for Haematology,
100 White Lion Street, London N1 9PF, UK.
E-mail bcsh@b-s-h.org.uk
First published online 26 June 2015
doi: 10.1111/bjh.13556
embolism (VTE). Less well understood are the mechanisms
behind the increased risk of developing cancer at times far
removed, often years after thrombosis, that has been described
in large population studies (Baron et al, 1998). It is likely that
this reflects shared risk factors for development of both cancer
and thrombosis such as, for example, smoking and obesity.
The expression of tissue factor on tumour cells and the pro-
thrombotic properties of mucins contribute to the thrombosis
risk in malignancy. In addition there is evidence that tissue
factor expression, which may result from proto-oncogene
expression and tumour suppressor gene inhibition, confers a
pro-angiogenic state, which may enhance the aggressiveness
and invasiveness of cancers. Malignancy itself, surgery,
indwelling intravenous catheters, chemo-radiotherapy and
intercurrent medical complications, such as infection, all con-
tribute to the increased risk of thrombosis in cancer patients.
Thrombotic events rank second only to the direct effects of
cancer as a cause of death in cancer patients (Khorana, 2010).
Several studies have assessed differences in the risk of
thrombosis between cancers. Several tumour sites, including
lung, brain, pancreas, stomach, ovary and kidney, and also
lymphoma have the strongest reported association with
thrombosis development (Agnelli, 1997; Baron et al, 1998).
Most studies confirm that the development of VTE in
patients with cancer is associated with a poorer prognosis
than that seen in thrombosis-free cancer patients and this
was confirmed in all 12 tumour types in one study (Chew
et al, 2006). Whether this is related to the effects of throm-
bosis or reflects inherent tumour aggressiveness is not clear.
It has also been observed that cancer patients with VTE have
poorer outcomes as judged by the need for hospital admis-
sion, higher rates of major bleeding and higher rates of
thrombosis recurrence on anticoagulant therapy compared
with patients who do not have cancer (Levitan et al, 1999;
Palareti et al, 2000; Prandoni et al, 2002; Trujillo-Santos
et al, 2008).
Thromboprophylaxis and cancer
Since 2007, it has been routine care to perform a risk assess-
ment for thrombosis on all hospitalized patients in the UK
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British Journal of Haematology, 2015, 170, 640–648

(Department of Health, 2007; National Institute for Health
and Clinical Excellence (NICE) 2010). In practice, patients
with active cancer admitted for medical or surgical reasons,
should be offered pharmacological thromboprophylaxis
except where the likely benefit is outweighed by the associ-
ated bleeding risk (Kahn et al, 2012). For these purposes
active cancer should be considered to include a diagnosis of
cancer, other than basal cell or squamous cell carcinoma of
the skin, within the previous 6-month period, and any treat-
ment for cancer within the previous 6-month period or
recurrent or metastatic cancer (Lee et al, 2003).
A number of studies have investigated the use of routine
thromboprophylaxis in ambulatory cancer outpatients receiv-
ing chemotherapy. A Cochrane review of 9 randomized
controlled trials (RCTs) involving 3538 patients, which com-
pared patients receiving thromboprophylaxis [eight low
molecular weight heparin (LMWH) and one warfarin] with
control groups, found a reduction in VTE risk [relative risk
(RR) 0
66 (0
41–0
93)] without a significant increased risk of
bleeding [RR 1
57 (0
69–3
6)] (Di Nisio et al, 2012). How-
ever, this analysis identified that 60 patients needed to be
treated to prevent 1 episode of thrombosis, suggesting that
thromboprophylaxis should not be used routinely in outpa-
tients with cancer but should be considered in individuals at
very high thrombotic risk. Identification of these high risk
patients can be aided by the use of risk assessment scores,
such as that developed by Khorana et al (2008) (Table I)
which identifies as higher risk patients with stomach, pan-
creas, lung, gynaecological, bladder or testicular cancer or
lymphoma as well as the presence of a platelet count
Table I. Predictive model for chemotherapy-associated venous
thromboembolism.
Patient characteristic Risk score
Site of cancer
Very high risk (stomach, pancreas) 2 phylaxis (2B).
High risk (lung, lymphoma, gynaecological, 1  Outpatients with active cancer should be assessed for
bladder, testicular)
Pre-chemotherapeutic platelet count ≥350 9 109/l 1 require thromboprophylaxis, it should be considered for
Haemoglobin concentration <100 g/l or use 1 high risk patients (2B).
of erythropoiesis-stimulating agents
Pre-chemotherapeutic leucocyte count >11 9 109/l 1
Body mass index ≥ 35 kg/m2 1
Thrombosis rate
per 2
5 months (%)
Low score 0 0
3–0
8
Intermediate score 1–2 1
8–2
High score >2 6
7–7
1
This table has been modified from research originally published in
Blood. Khorana, A.A., Kuderer, N.M., Culakova, E., Lyman, G.H. &
Francis, C.W. (2008) Development and validation of a predictive
model for chemotherapy associated thrombosis. Blood, 111, 4902–
4907. © the American Society of Hematology.
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British Journal of Haematology, 2015, 170, 640–648
Guideline
>350 9 109/l, haemoglobin concentration <100 g/l, leucocyte
count pre-chemotherapy >11 9 109/l and a body mass index
of >35 kg/m2 (Khorana et al, 2008). Alternatively, an inter-
national practice guideline, whilst also not recommending
routine prophylaxis, suggests consideration in patients with
locally advanced or metastatic pancreatic and lung cancer
who are not deemed at excessive risk for bleeding (Farge
et al, 2013).
There is a well-recognized association between multiple
myeloma and VTE, which is further increased in patients
treated with thalidomide or lenalidomide. The role of throm-
boprophylaxis in this setting has been reviewed recently in
two BCSH guidelines, which recommend risk assessment and
treatment with low dose aspirin if low risk and LMWH or
dose-adjusted warfarin if non-low risk. Thromboprophylaxis
should be continued until disease control is achieved (Bird
et al, 2011; Snowden et al, 2011). The role of the new oral
anticoagulants dabigatran, rivaroxaban, apixaban and edox-
aban as prophylaxis in cancer patients has not yet been
determined.
Surgical prophylaxis
Recently, a move towards extended prophylaxis for high-risk
surgical patients, such as those requiring surgery for the
management of abdominal and pelvic cancer, has developed.
This treatment should be considered for certain groups of
patients (NICE, 2010).
Recommendations
 Patients with active or recent cancer admitted to hospi-
tal should receive thromboprophylaxis throughout their
admission unless contraindicated (2C).
 Patients undergoing abdominal and pelvic surgery for
cancer should be considered for extended thrombopro-
thrombosis risk and although most do not routinely
 Patients with myeloma receiving thalidomide or lenalid-
omide should be risk-assessed for VTE and offered
thromboprophylaxis unless there is a contraindication
(1A).
 Thromboprophylaxis should be reviewed in patients
with thrombocytopenia. A platelet count of <50 3 109/l
is a relative contraindication to pharmacological pro-
phylaxis (1C).
Prevention of catheter-related thrombosis
A prospective study of 82 patients reported that fixed, low
dose warfarin was very effective in reducing the risk of
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Guideline
catheter-related thrombosis (Bern et al, 1990). More recently,
however, the WARP (Warfarin thromboprophylaxis in cancer
patients with central venous catheters) trial, which random-
ized 812 patients to warfarin or no therapy found no differ-
ence in the risk of catheter-related thrombosis between the
two groups (Young et al, 2009). A Cochrane review evalu-
ated the efficacy of oral and parenteral anticoagulants in the
prevention of central venous catheter-related thrombosis
reported up to February 2010. Neither warfarin nor prophy-
lactic dose LMWH was associated with reduction in risk (Akl
et al, 2011a).
Recommendation
 Routine use of anticoagulants at prophylactic or thera-
peutic dose to prevent catheter-related thrombosis in
cancer patients is not recommended (1A).
Thromboprophylaxis in patients on long-term
prothrombotic anti-cancer therapies
Some patients will have no evidence of active malignant dis-
ease but benefit from long term adjuvant treatment with
agents such as tamoxifen. In the large (16 289 women) Dan-
ish registry of women taking tamoxifen after treatment for
breast cancer, the 5-year incidence of VTE was 1
2% vs.
0
5% for those not taking tamoxifen, with the highest risk of
thrombosis in older women and in the first 2 years of treat-
ment [RR 3
5; 95% confidence interval (CI) 2
1–6
0] (Her-
nandez et al, 2009). Although the RR is elevated, the
absolute risk is not sufficiently high to warrant concomitant
prophylactic anticoagulation. A systematic review of adjuvant
hormone therapies produced similar conclusions (Deitcher &
Gomes, 2004). In women who have had cancer-associated
thrombosis and who require longer term treatment with
tamoxifen, it may be reasonable to continue with anticoagu-
lation for the duration of the adjuvant therapy.
Recommendation
 Patients without a history of VTE receiving adjuvant
hormonal therapies for cancer should not routinely
receive thromboprophylaxis (1B).
Anticoagulants and thromboprophylaxis to prolong
cancer survival
Some early observations suggested that antithrombotic drugs
may prolong survival in cancer patients. Two Cochrane sys-
tematic reviews have been published in the area. The first
(Akl et al, 2011b) evaluated the evidence comparing oral an-
ticoagulants, at a variety of intensities with no treatment or
prophylactic treatment. Although warfarin reduced the inci-
dence of VTE at the expense of higher rates of minor and
642
major bleeding, there was no effect on survival (Akl et al,
2011b). The second Cochrane review published in 2011
examined studies comparing periods of unfractionated hepa-
rin (one study) or LMWH (eight studies) at different doses
and for different periods of time versus placebo or no treat-
ment (Akl et al, 2011c). A survival benefit was observed at
24 months but not at 12 months, accompanied by a signifi-
cant reduction in VTE without an increase in bleeding (Akl
et al, 2011c). More recently, no difference in survival was
found in an RCT of patients with advanced malignancy that
compared LMWH with placebo (van Doormaal et al, 2011a).
Recommendation
 Antithrombotic use aimed solely at increasing life expec-
tancy in patients with cancer but without a history of
VTE, is not recommended (1A).
Treatment of symptomatic cancer-associated
VTE
Initial treatment (up to 6 months)
Patients with cancer-associated VTE have a higher risk of
recurrence on treatment than those without cancer (Pran-
doni et al, 2002). The CLOT trial (Lee et al, 2003) demon-
strated that treatment of cancer-associated VTE with
6 months of LMWH resulted in a significantly lower recur-
rence rate at 6 months than conventional treatment with
International Normalized Ratio-adjusted warfarin [7
9% vs.
15%, Hazard ratio (HR) = 0
48; 95% CI, 0
30–0
77]. The
superiority of continued LMWH treatment over LMWH fol-
lowed by a vitamin K antagonist (VKA) is supported by two
other studies (Meyer et al, 2002; Hull et al, 2006). In the
CLOT study full dose dalteparin was given for 1 month fol-
lowed by a reduced dose (75–80%) for months 2–6 (Lee
et al, 2003). In the other two studies full dose tinzaparin or
enoxaparin was given for 3 months (Meyer et al, 2002; Hull
et al, 2006). None of the studies showed any excess of bleed-
ing associated with continued LMWH. There are no direct
comparisons of 3 months vs. 6 months of treatment.
Problems associated with the use of warfarin, such as
numerous drug interactions, the effect of diet, oral route of
administration and slow onset and offset of action, make it
difficult or unsuitable for the management of patients with
malignancy. On the other hand, possible barriers to LWMH
use are the need for subcutaneous injection and impaired
renal function. Therapeutic dose LMWH should be used
with some caution in patients with renal impairment and
dose reduction or anti-Xa monitoring may be indicated in
patients with estimated creatinine clearance <30 ml/min or
very low body weight. Unfractionated heparin can be used
for initial treatment, but is not practical for prolonged out-
patient therapy. We suggest warfarin for maintenance in this
circumstance.
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British Journal of Haematology, 2015, 170, 640–648

The trials of dabigatran, rivaroxaban, apixaban and edox-
aban or directly acting oral anticoagulants (DOACs) for
treatment of VTE contained only small numbers of patients
with cancer. Subgroup analysis suggests they may have simi-
lar efficacy to warfarin but no comparison with LMWH has
been made (van der Hulle et al, 2014). The DOACs have
many of the logistical advantages of LMWH in these patients
undergoing active treatment. For patients who cannot have
or tolerate subcutaneous LMWH we suggest warfarin or a
DOAC.
Thrombosis recurrence during treatment
Thrombosis recurrence during treatment is reported in 6–9%
of cancer-associated VTE patients receiving LMWH and 10–
17% of those receiving warfarin (Lee, 2012). There is limited
evidence regarding the management of recurrence of throm-
bosis in patients with cancer on active anticoagulant treat-
ment. Recurrence in patients taking warfarin should be
managed by switching to LWMH. Those patients using
LMWH at approximately 75% of the normal therapeutic
dose, which is usual practice after the first month of treat-
ment, should increase to the full weight-based therapeutic
dose. For those already receiving full dose LMWH, there is
some evidence to support further increasing the dose of
LMWH by 20–25% (Carrier et al, 2009). If there is contin-
ued evidence of clot extension, then an option is to increase
the LMWH dose guided by anti-Xa measurement. A sug-
gested regimen is to aim for a peak anti-Xa level of 1
6–
2
0 u/ml for once daily LMWH and 0
8–1
0 u/ml peak for
twice daily treatment (Carrier et al, 2009, 2013; Lee, 2012).
The benefit of dividing higher doses is uncertain but in the
only comparative trial, there was a trend in the cancer sub-
group for lower recurrence using twice daily compared to
once daily enoxaparin with no significant increase in bleed-
ing (Merli et al, 2001).
Insertion of an inferior vena cava (IVC) filter is not rec-
ommended for recurrence alone. An increased risk of VTE
recurrence has been shown in cancer patients, despite IVC
filter use (Elting et al, 2004). In non-cancer patients, routine
use of IVC filters reduces pulmonary embolism (PE) but
increases deep vein thrombosis (DVT) and has no impact on
overall survival over an 8-year follow-up [The Pr
evention du
Risque d’Embolie Pulmonaire par Interruption Cave (PRE-
PIC) Study Group, 2005].
Long-term (>6 months) therapy
The role of anticoagulation after 6 months of treatment has
not been extensively studied. It is likely that LMWH is more
effective than VKA in patients with active malignancy but
the optimal dose in this situation is not clear. With progres-
sive disease, quality of life and the patient’s wishes should be
considered, because the risk of thrombosis increases with
metastatic disease (Wun & White, 2009). It is reasonable to
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British Journal of Haematology, 2015, 170, 640–648
Guideline
consider an alternative oral anticoagulant if the patient does
not wish to continue with daily injections after 6 months
and in these circumstances oral direct inhibitors of coagula-
tion factors may offer advantages over warfarin for the rea-
sons stated above. There is little evidence for loss of bone
density in situations where LMWH has been used for pro-
longed periods of time (Rodger et al, 2007).
If treatment is thought to have eradicated the malignant
disease then anticoagulation can reasonably be discontinued
after 6 months. Risk prediction measurements, such as D-
dimer, have not been evaluated in this circumstance but
stage IV cancer, brain lung, ovarian, gastrointestinal and
multiple active cancers, along with myeloproliferative and
myelodysplastic disorders, neurological disease with leg pare-
sis and stage III cancers, were all found to predict the risk of
recurrence of VTE in patients with a first cancer-associated
thrombosis following discontinuation of a finite period of
anticoagulation (Chee et al, 2014).
Thrombocytopenia. The presence of thrombocytopenia
demands reassessment of the risk-benefit balance of anticoag-
ulation. However, in the first 3 months after thrombosis the
risk of recurrence is particularly high and so every effort
should be made to allow safe administration of anticoagulant
therapy. Consensus suggests that full anticoagulation is with-
out excessive risk whilst the platelet count remains above
50 9 109/l (Carrier et al, 2013). One approach is to attempt
to support the platelet count to allow full dose anticoagula-
tion to continue throughout the period of highest risk of
recurrence of the VTE. Temporary insertion of an IVC filter
is warranted if persistent thrombocytopenia or other bleeding
risk precludes anticoagulation. Heparin-induced thrombocy-
topenia must be excluded in patients developing thrombocy-
topenia during heparin therapy.
If the platelet count cannot be elevated then 50% dose
LMWH can be given to patients with a platelet count of 25–
50 9 109/l. Below this level we advise withholding anticoagu-
lation, although prophylactic doses have been used with
reported benefit (Drakos et al, 1992).
Recommendations
 In patients with cancer-associated thrombosis initial
treatment should be with LMWH for 6 months, if toler-
ated (1A).
 Warfarin and other oral anticoagulants are acceptable
alternatives if LMWH is impractical and anticoagulation
is indicated (1A).
 An IVC filter should only be inserted when there is a
strong contraindication to anticoagulation and should
be removed if possible as soon as anticoagulation is pos-
sible (2C).
 In the presence of active malignancy, anticoagulation
should be continued, taking patient status and wishes
and bleeding risk into consideration. There is a ratio-
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Guideline
nale but little direct evidence for preferring to continue
to use LMWH (2B).
 When the platelet count is <50 3 109/l platelet support
should be given to elevate the count to >50 3 109/l to
allow full dose anticoagulation, especially in the imme-
diate period following thrombosis development (2D).
 Patients with platelet counts between 25 and 50 3 109/l
should have frequent assessment to allow decisions on
LMWH to be made (2D).
 If the platelet count remains <25 3 109/l, full anticoag-
ulation should be avoided (1D).
Incidental venous thrombosis
Asymptomatic venous thrombosis is a relatively common
finding in high risk patients screened for DVT or PE (Mei-
gnan et al, 2000). In a meta-analysis of 12 studies reported
between 1996 and 2007, including over 10 000 chest comput-
erized tomography (CT) scans being undertaken for reasons
other than suspicion of PE, the estimated prevalence of inci-
dental PE was 2
6% (95% CI 1
9–3
4) (Dentali et al, 2010).
Incidental PE rates were higher in cancer patients (odds ratio
1
80, 95% CI 1
18–2
75) who had a weighted mean preva-
lence of 3
1% (95% CI 2
2–4
1), and were more often
detected when CT scanning with a slice thickness of <5 mm.
Furthermore, if a CT pulmonary angiography protocol (with
slice thickness of ≤1
5 mm) was systematically included when
undertaking cancer-staging CT of thorax, 18/407 patients
(4
4%) were found to have incidental PE, 7 of which were
not detected on standard CT (Browne et al, 2010).
The Haemostasis and Malignancy Scientific Sub-Commit-
tee of the International Society on Thrombosis and Haemo-
stasis (Khorana et al, 2012) recommend the term ‘incidental’
rather than ‘asymptomatic’ because in 40–50% of these cases
patients will have PE-related symptoms that have either been
overlooked or attributed to their cancer (O’Connell et al,
2006; Sahut D’Izarn et al, 2012; Shteinberg et al, 2012). Most
studies comparing incidental PE with symptomatic PE report
similar underlying risk factors, such as advanced cancer stage
(Cronin et al, 2007; Browne et al, 2010; Dentali et al, 2010;
Di Nisio et al, 2010; Font et al, 2011; Sahut D’Izarn et al,
2012) and a similar distribution of pulmonary arteries
affected, with around 50% involving main or lobar arteries
and only 10–13% being sub-segmental PE (O’Connell et al,
2006; Sahut D’Izarn et al, 2012; Shteinberg et al, 2012; den
Exter et al, 2013a). However symptomatic patients more
often have bilateral PE (Font et al, 2011) and a have a higher
overall thrombotic burden (den Exter et al, 2013b).
The natural history of incidental PE in cancer patients has
been poorly studied. Higher 6-month mortality in cancer
patients with venous thrombosis has been demonstrated to
be independent of whether the thrombosis is symptomatic or
incidental (Dentali et al, 2011). A retrospective case control
study comparing 70 patients with incidental PE with 137
644
cancer patients without venous thrombosis, but matched for
age, cancer type and stage, demonstrated a higher 6-month
mortality (HR 1
97, 95% CI 1
09–3
58) in the incidental PE
patients (O’Connell et al, 2011). Studies comparing out-
comes in cancer patients with incidental PE to those with
symptomatic PE (when both receive anticoagulant therapy),
suggest a similar risk of symptomatic recurrent thrombosis,
major bleeding and mortality (den Exter et al, 2011; Sahut
D’Izarn et al, 2012). Font et al (2011) noted a slightly higher
recurrent thrombosis rate, but no difference in overall sur-
vival, in cancer patients with symptomatic DVT or PE com-
pared to those with initial incidental DVT or PE, despite the
latter receiving a shorter period of anticoagulation.
Incidental DVT in cancer patients undergoing a staging
CT scan of abdomen and pelvis involving IVC, iliac, com-
mon femoral or splanchnic veins may be as common as inci-
dental PE (Cronin et al, 2007; Di Nisio et al, 2010; Douma
et al, 2010). A review of 2591 consecutive abdominal CT
scans (Ageno et al, 2012) identified incidental abdominal
vein thrombosis most commonly in patients with cirrhosis.
The prevalence of incidental abdominal vein thrombosis was
2
5% among 1442 cancer patients (95% CI 1
78–3
48).
Patients with gastro-intestinal tract malignancy appear to
have a particularly high rate for incidental abdominal or
lower limb DVT (Singh et al, 2010).
Retrospective short term follow-up of small cohorts of
patients with incidental PE or DVT who did not receive anti-
coagulant therapy because the thrombosis was missed in the
initial CT report or because the patient was deemed to be at
high bleeding risk, show a symptomatic recurrent thrombosis
risk of 5–11% within 3 months (Gladish et al, 2006; Browne
et al, 2010; Douma et al, 2010). In a retrospective review of
113 lung cancer patients with incidental PE, 62 who did not
receive anticoagulant treatment had a higher mortality rate
(HR 4
1, 95% CI 2
3–7
6) despite both groups having similar
cancer stage and performance status (Sun et al, 2010).
Given the absence of randomized studies of anticoagulant
therapy in cancer patients with incidental venous thrombosis,
optimal management remains unknown. However the low
quality evidence available suggests that, in cancer patients,
incidental PE and DVT are indicative of a generalized pro-
thrombotic state and can be associated with a significant risk
of early recurrent thrombosis and similarly poor survival rate
as symptomatic thrombosis. Current American College of
Chest Physicians guidance favours anticoagulant therapy for
incidental venous thrombosis where the diagnosis is secure
(Kearon et al, 2012). The one exception may be patients with
isolated sub-segmental PE, which may have a more benign
natural history (Eyer et al, 2005), but there is no clear con-
sensus on this at present (den Exter et al, 2013c). The merits
of anticoagulation for symptomatic abdominal vein throm-
bosis require individual risk assessment (Tait et al, 2012),
and it is recommended that cancer patients with incidental
abdominal vein thrombosis are considered similarly.
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British Journal of Haematology, 2015, 170, 640–648

Recommendations
 Cancer patients with incidental pulmonary embolus or
DVT should be therapeutically anticoagulated as for
symptomatic disease (1C).
Screening for cancer in patients with
apparently unprovoked VTE
The association of cancer and VTE is well recognized. A sys-
tematic review of 14 studies and an additional abstract (Car-
rier et al, 2008) reported the prevalence of undiagnosed
cancer in patients with unprovoked VTE as 6
1% (95% CI
5
0–7
1) at presentation, increasing to 10
0% (CI 8
6–11
3)
at 12 months. This review suggests that an extensive screen-
ing strategy using CT of the abdomen and pelvis increases
the detection rate of previously undiagnosed cancer from
49
4% (CI 40
2–58
5) to 69
7% (CI 61
1–77
8). The further
question is whether earlier cancer detection affects outcomes
for patients in these clinical circumstances.
In the SOMIT (Screening for Occult Malignancy in
Patients with Symptomatic Idiopathic VTE) study, 99
patients were randomized to extensive screening for occult
cancer and 102 to no further testing (Piccioli et al, 2004).
Extensive screening identified occult cancer in 13 (13
1%)
patients, with a single (1
0%) further malignancy becoming
apparent during the 2-year follow-up. In the control group a
total of 10 (9
8%) malignancies became apparent during the
2-year follow-up. Mean delay to diagnosis was reduced from
11
6 to 1
0 month (P < 0
001). Cancer-related mortality dur-
ing the 2-year follow-up period occurred in two (2
0%) of
the 99 patients in the extensive screening group versus four
(3
9%) of the 102 control patients [non-significant absolute
difference 1
9% (95% CI 5
5–10
9)].
A year after publication, the data from the SOMIT trial
were used to perform a decision analysis (Di Nisio et al,
2005). The screening tests were divided into several possible
strategies and the number of detected cancers and the number
of patients investigated further for what eventually turned out
to be a benign condition were calculated for each strategy. As
an example, CT of the abdomen combined with sputum
cytology and mammography detected 12 of the 14 patients
with cancer and had one false-positive result. The authors
concluded that screening for cancer with a strategy including
abdominal/pelvic CT with or without mammography and/or
sputum cytology appears potentially useful although its cost-
effectiveness needs confirmation in a large trial.
NICE further examined these data and, without consider-
ing further data from the larger non-randomized study dis-
cussed below, concluded that a strategy based on abdominal/
pelvic CT plus mammography seemed to provide the best
value-for-money leading to a (weak) recommendation to
‘consider further investigations for cancer with an abdomi-
no-pelvic CT scan (and a mammogram for women) in all
patients aged over 40 years with a first unprovoked DVT or
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British Journal of Haematology, 2015, 170, 640–648
Guideline
PE who do not have signs or symptoms of cancer based on
initial investigation’ (NICE, 2012).
A larger, prospective cohort study compared limited and
extensive cancer screening strategies (Van Doormaal et al,
2011b); all patients underwent baseline screening consisting
of history, physical examination, basic laboratory tests and
chest X-ray. Of the 630 patients studied, 342 were seen in
hospitals that performed additional extensive screening with
CT chest/abdomen and mammography and 288 in hospitals
that did not. The initial limited screening detected malig-
nancy in 12/342 (3
5%) and 7/288 (2
4%) respectively. In
hospitals performing extensive screening, 302 of the 330
remaining patients underwent screening and suspicion of
cancer was raised in 91 (30% of 302) and confirmed in six
(2
0% of the 302), of which three were potentially curable.
During a median 2
5 years of follow-up, cancer was diag-
nosed in an additional 12 patients in the extensive screening
group and an additional 14 patients in the limited screening
group. In the extensive screening group 26 patients (7
6%)
died compared with 24 (8
3%) in the limited screening
group; adjusted HR 1
22 (95% CI 0
69–2
22). Of these
deaths, 17 (5
0%) in the extensive screening group and 8
(2
8%) in the limited screening group were cancer-related;
adjusted HR 1
79 (95% CI 0
74–4
35). Although this study
was abandoned as futile, the authors concluded that the low
yield of extensive screening and lack of survival benefit do
not support routine screening for cancer with abdominal and
chest CT scan and mammography in patients with a first epi-
sode of unprovoked VTE.
Clinicians are left in a difficult situation as it appears that
screening does identify malignancies at an earlier stage
(Monreal et al, 2004; Piccioli et al, 2004) but cancer diag-
nosed at the same time as, or within 1 year after, an episode
of VTE is associated with an advanced stage of cancer and a
poor prognosis (Sorensen et al, 2000). Extensive screening,
and even counselling patients about screening, can cause
considerable anxiety. Further radiology-based screening
results in radiation exposure [a CT abdomen is the equiva-
lent of 400 chest X-rays and 3
3 years of background radia-
tion (Davies et al, 2011)] and unnecessary further testing in
those with false positive results.
Cancer is more prevalent in those with bilateral DVTs
(Rance et al, 1997), early VTE recurrence (Prandoni et al,
1992), or very high D-dimers [>4000 lg/l fibrinogen equiva-
lents units (FEU) (Beckers et al, 2006; Schutgens et al, 2005),
>8000 lg/l FEU (Paneesha et al, 2006)], and if universal
screening is not implemented these may be may useful in
selecting those for further investigation.
Recommendations
 In patients over 40 years old with unprovoked VTE,
screening for cancer with CT scan (and mammography
for women) should be considered but not routinely per-
formed (2C).
645
Guideline

 There should be a lower threshold for screening those All of the authors were involved in the production of the
with bilateral DVT, very high D-dimers or an early final document. HGW chaired the guideline group; the other
recurrence of VTE (2C). authors are all BCSH Haemostasis and Thrombosis Taskforce
representatives. The members of the BCSH Haemostasis and
Thrombosis Taskforce at the time of the development of the
Review process guidance were those above along with: Elaine Gray, clinical
scientist, NIBSC; Ian Jennings, clinical scientist, UK NEQAS
Members of this writing group will inform the writing group
coagulation; Isobel Walker, medical director, UK NEQAS
chairman if any new pertinent evidence becomes available
coagulation; and Andrew Mumford, Senior Lecturer in Hae-
that would alter the strength of the recommendations made
matology, University of Bristol. The authors would like to
in this document or render it obsolete. The document will
thank them and the BSH sounding board for their help in
be archived and removed from the BCSH current guidelines
producing this guidance.
website if it becomes obsolete. If new recommendations are
made, an addendum will be published on the BCSH guide-
lines website (http://www.bcshguidelines.com/). If minor Disclaimer
changes are required due to changes in level of evidence or
While the advice and information in this guidance is believed
significant additional evidence supporting current recom-
to be true and accurate at the time of going to press, neither
mendations a new version of the current guidance will be
the authors, the British Committee for Standards in Haema-
issued on the BCSH website.
tology or the publishers accept any legal responsibility for
the content of this guidance.
Acknowledgements
HGW, DK, ML, RCT and MM performed the review and
took responsibility for writing individual sections of the text.

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