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Risk and prevention of venous thromboembolism in adults


with cancer
Author: Kenneth A Bauer, MD
Section Editor: Lawrence LK Leung, MD
Deputy Editor: Jennifer S Tirnauer, MD

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: Aug 2019. | This topic last updated: Jul 15, 2019.

INTRODUCTION

Individuals with cancer are at risk for thrombotic complications due to a hypercoagulable state. The
spectrum of hemostatic abnormalities ranges from abnormal coagulation tests in the absence of
clinical manifestations, to massive or fatal thromboembolism. Thrombosis may precede the
diagnosis of malignancy by months, or it may only occur during treatment or hospitalization.
Individuals with cancer may also have a higher risk of bleeding with anticoagulation, making
decisions about the use of prophylactic anticoagulants more challenging.

Here we discuss the risks of venous thromboembolism (VTE), which typically presents as deep
vein thrombosis (DVT) and/or pulmonary embolism (PE), in adults with cancer, as well as the
primary prevention of VTE in these individuals. The following are discussed in detail separately:

● Treatment and secondary prevention of VTE in adults with cancer – (See "Anticoagulation
therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary
embolism) in adult patients with malignancy" and "Catheter-related upper extremity venous
thrombosis" and "Multiple myeloma: Prevention of venous thromboembolism in patients
receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)

● Prevention and treatment of thromboembolism in children with cancer – (See


"Thromboembolism in children with cancer".)

● Evaluation for occult malignancy in patients with VTE – (See "Evaluating adult patients with
established venous thromboembolism for acquired and inherited risk factors", section on
'Evaluation for occult malignancy'.)

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INCIDENCE AND RISK FACTORS

VTE is a common complication of malignancy. In most cases, thromboembolic events occur in the
setting of a clinically evident malignancy [1,2]. However, some patients who present with VTE are
only found to have a malignancy at the time the VTE occurs or months later. Despite the high
frequency of VTE in individuals with cancer, it is important to remember that most individuals with
cancer do not develop VTE.

Overall risk of VTE in individuals with cancer — Clinically apparent VTE occurs in as many as
10 percent of patients with cancer [3-6]. Autopsy series have described even higher rates of
thrombosis for certain tumor types. One study, for example, found evidence of thrombosis in 30
percent of patients who died of pancreatic cancer; the incidence was over 50 percent in those with
tumors in the body or tail of the pancreas [7].

The tumor type, location, stage, and time since diagnosis influence VTE risk, along with patient
comorbidities and certain cancer therapies [8-14]. Our approach to estimating VTE risk
distinguishes between individuals who are hospitalized or outpatient. Within those groups, risk is
affected by the following factors:

● Tumor-specific factors – Tumor cells can express procoagulant activity that induces
thrombin generation; in addition, the patient's non-cancerous tissues may express
procoagulant activity in response to the tumor. Blood-borne tissue factor in microparticles may
play a role in the pathogenesis of the hypercoagulable state accompanying cancer. (See
"Pathogenesis of the hypercoagulable state associated with malignancy".)

● Anatomic factors – Some tumors increase VTE risk by externally compressing or directly
invading large vessels. As examples, renal cell carcinoma infiltrates the inferior vena cava in 5
to 9 percent of patients [15]; hepatocellular carcinoma can compress or invade the hepatic
vein; and large mediastinal tumors or bulky axillary lymphadenopathy can compress upper
extremity veins, leading to thrombosis. Large abdominal/pelvic tumors can compress major
veins leading to deep venous thrombosis in the legs [16,17]. (See "Clinical manifestations,
evaluation, and staging of renal cell carcinoma" and "Clinical features and diagnosis of
hepatocellular carcinoma" and "Primary (spontaneous) upper extremity deep vein
thrombosis".)

● Patient-specific factors – VTE risk is increased in patients with prior VTE, advanced age,
obesity, and inherited thrombophilia [8,18-29]. In contrast, smoking does not appear to
significantly increase risk.

● Therapy-associated factors – Some chemotherapy agents and high risk surgeries (eg, large
intraabdominal or pelvic procedures) increase VTE risk. (See "Drug-induced thrombosis in

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patients with malignancy" and "Toxicity of molecularly targeted antiangiogenic agents:


Cardiovascular effects".)

The overall risk of VTE per patient is greater in inpatients, but the vast majority of VTE events
occur in outpatients (around 80 percent) because most patients with cancer are treated in the
outpatient setting [30].

Inpatients (VTE risk) — An estimate of the magnitude of VTE risk in inpatients with cancer was
obtained from a review of the records of eight million individuals in the United States over age 65
(patients receiving Medicare) who were admitted to a hospital between 1988 and 1990 [31].
Compared with those who did not have a malignancy, patients with a diagnosis of malignancy had
a greater incidence of VTE during the initial hospitalization (0.60 versus 0.57 percent, a statistically
significant difference). In this study, the malignancies with the highest rates of VTE were cancers of
the ovary, brain, pancreas, and lymphoma [31]. Malignancies associated with the greatest absolute
number of episodes of VTE were cancers of the lung, colon, and prostate, due to the relatively high
frequency of these cancers in the population.

In a Danish cohort of 57,591 individuals with cancer hospitalized for VTE, the incidence rates of
VTE were highest in individuals with cancer of the pancreas, brain, liver, multiple myeloma, and
any form of advanced-stage cancer (incidence rates: 41, 18, 20, 23, and 28, respectively) [11].

Some cancer surgeries, especially large intraabdominal or pelvic procedures, are associated with
a higher risk of VTE than other types of surgery (eg, mastectomy). This was demonstrated in a
review of 43,808 cancer surgeries from a surgical database, which found that the risk of VTE was
highest in patients undergoing esophagectomy, followed by cystectomy, pancreatectomy,
gastrectomy, colectomy, lung cancer surgery, and hysterectomy [13].

The effect of patient comorbidities on postoperative VTE risk was demonstrated in a review of
43,808 patients undergoing cancer surgery [13]. The following factors were found to be significant
predictors for the development of VTE on multivariate analysis:

● Increased age
● Recent steroid use
● Body mass index (BMI) ≥35 kg/m2
● Postoperative complications (eg, wound infection, reintubation, cardiac arrest, sepsis)
● Longer hospitalization (>1 week)

Additional risk factors for VTE following cancer surgery were illustrated in a review of 44,656
patients undergoing surgery for solid tumors [32]. The overall risk of VTE was 1.6 percent. The
following findings were associated with increased risk of postoperative VTE:

● Age ≥65
● Metastatic disease

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● Ascites
● Congestive failure
● BMI ≥25 kg/m2
● Platelet count >400,000/microL
● Serum albumin <3 g/dL
● Duration of surgery >2 hours

In this study, one-third of the VTE events occurred after hospital discharge, and 30-day mortality
was more than six-fold higher in patients with VTE than in those without VTE (8.0 versus 1.2
percent, respectively). The high rates of VTE after hospital discharge and high VTE-associated
mortality support a longer duration of postoperative anticoagulation in patients with cancer than
that used for individuals without cancer. (See 'Surgical patients' below.)

Outpatients (VTE risk) — A number of studies suggest that the incidence of VTE is highest during
the first year after a cancer diagnosis, during chemotherapy, and in those with advanced disease.
As examples:

● In a Danish cohort study of 57,591 individuals with cancer, the incidence of VTE was highest
within the first year after cancer diagnosis (incidence rate: 15.0 versus 8.6) [11].

● A study of 235,149 cancer cases from a United States cancer registry reported a diagnosis of
VTE in 3775 (1.6 percent); 12 percent of VTE events occurred at the time of diagnosis [9].
Additional findings included the following:

• The incidence of VTE was higher during the first year of follow-up than the second year
for virtually all types and stages of cancer

• Metastatic disease at the time of diagnosis was the strongest predictor for the
development of VTE

• The diagnosis of VTE was a significant predictor for decreased survival during the first
follow-up year for all cancer types (median overall relative risk: 3.7)

● In a study of 68,142 patients with colorectal cancer, the two-year cumulative incidence of VTE
was 3.1 percent [10]. Events per 100 person-years during the first six months, second six
months, and second year were 5.0, 1.4, and 0.6, respectively. Other findings included:

• Significant predictors of VTE included metastatic disease and the presence of three or
more comorbid conditions

• In risk-adjusted models, VTE was a significant predictor of death within one year of
cancer diagnosis among patients with local or regional disease, but not among those with
metastatic disease

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● In a retrospective study of 497,180 Taiwanese patients with cancer, VTE risk was over 10-fold
higher than the reported incidence in the general Taiwanese population (185 versus 15.9
cases per 100,000 person-years, respectively) [33]. VTE risk was greater in those with prior
history of VTE; multiple myeloma, prostate cancer, lung cancer, gynecologic cancer, sarcoma,
or metastasis of unknown origin; and female sex in patients age 40 to 80 years. VTE risk was
lower among patients >80 years, and those with head and neck, endocrine, esophageal, or
breast cancer.

● The SAVE-ONCO trial, which randomized 3212 ambulatory outpatients with cancer to receive
the ultra-low molecular weight heparin semuloparin versus no anticoagulation for VTE
prophylaxis, used a post-hoc analysis to identify patient factors associated with VTE [34].
Implicated factors included a central venous catheter, obesity, age >75 years, chronic
respiratory failure, chronic heart failure, venous insufficiency/varicose veins, and prior VTE.
The incidence of VTE was 12.5 percent in those with ≥3 of these risk factors, and 2.5 percent
in those with none of these features.

VTE risk also varies with the primary tumor type and is especially high with certain solid tumors
such as pancreatic cancer and brain tumors, as discussed separately. (See "Pathogenesis of the
hypercoagulable state associated with malignancy".)

Certain agents used in cancer therapy have been associated with increased risks of venous and
arterial thrombosis (eg, thalidomide, lenalidomide, tamoxifen, bevacizumab) [35]. These risks are
discussed in detail separately. (See "Drug-induced thrombosis in patients with malignancy" and
"Multiple myeloma: Prevention of venous thromboembolism in patients receiving
immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)".)

ASSOCIATION BETWEEN VTE AND MORTALITY

VTE is associated with increased morbidity and mortality in individuals with cancer in a variety of
settings (eg, unresectable tumor, curative resection) [36-39]. Causality has not been demonstrated,
however; and VTE may be a marker rather than an independent risk factor for early mortality. High-
quality data to support an improvement in mortality with anticoagulation are lacking. (See 'Effects
on survival' below.)

VTE-related deaths are especially common in those with exocrine pancreatic cancer. A systematic
literature review of patients with pancreatic cancer reported VTE incidences from 5 to 36 percent,
representing a 50-fold increase over the general population [39]. One of the studies reported on
1915 patients with pancreatic cancer treated with chemotherapy, in which 690 (36 percent)
developed a VTE [40]. Development of VTE, especially within 1.5 months of diagnosis, conferred a
greater likelihood of death (HR: 2.1; 95% CI 1.7-2.5).

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Cancer-associated VTE is associated with a higher mortality than VTE in the population without
cancer. This was shown in a review of eight million patients admitted to the hospital for VTE [31].
Those with concurrent malignancy had a 94 percent probability of death within six months,
whereas those without cancer had a 29 percent probability of dying within the same time period.

Of note, arterial thrombosis can account for a substantial number of deaths in individuals
undergoing chemotherapy. A review of 4466 ambulatory patients with cancer who were receiving
chemotherapy reported that thrombosis was one of the three most common causes of death [41].
The majority of the deaths related to thromboembolic disease were due to arterial thrombosis (eg,
myocardial infarction, stroke) rather than venous thromboembolism. Of the 141 deaths that
occurred during chemotherapy administration (3.2 percent), the three leading causes of death
were cancer progression (71 percent), infection (9 percent), and thromboembolic disease (9
percent total, 5.6 percent arterial, 3.5 percent venous).

PRIMARY PREVENTION

Overview of approach to prevention — The decision to use anticoagulation for primary


prevention takes into account the risk of VTE as well as the risk of bleeding from anticoagulants,
costs of medication, and mode of administration, which may negatively impact quality of life (eg,
need for injections). Patients are generally stratified according to whether they are inpatients
hospitalized for an acute medical illness or surgery, or ambulatory outpatients. Individuals with
cancer represent a particularly high-risk group in all of these settings. However, the benefit of
prophylactic anticoagulation is unclear in many subsets of patients [42,43].

● As a general rule, we use short-term anticoagulation during periods of high risk (eg,
hospitalization for acute medical illness, following major surgery), similar to patients without
cancer. Low molecular weight (LMW) heparin, unfractionated heparin, or fondaparinux are all
reasonable options. Direct oral anticoagulants (eg, rivaroxaban, apixaban) are options in
patients undergoing major orthopedic surgery (eg, total hip or knee replacement). The choice
among these agents depends on whether the patient is hospitalized or outpatient, cost,
availability, and other patient-specific factors. (See "Prevention of venous thromboembolic
disease in adult nonorthopedic surgical patients".)

● Warfarin generally is not used as prophylactic anticoagulation of relatively brief duration (ie,
days to a few weeks) in individuals with cancer, due to its delayed onset of antithrombotic
action along with its requirement for dose adjustment based on international normalized ratio
(INR) monitoring. Although the efficacy of LMW heparin is greater than warfarin for treatment
of cancer-associated VTE, its benefit over warfarin has not been demonstrated in the
prophylactic setting. (See "Anticoagulation therapy for venous thromboembolism (lower
extremity venous thrombosis and pulmonary embolism) in adult patients with malignancy",
section on 'Low molecular weight heparin'.)
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● Mechanical prophylaxis is an option for hospitalized patients with cancer for whom the risk of
bleeding is considered too high for anticoagulant use. (See "Prevention of venous
thromboembolic disease in acutely ill hospitalized medical adults", section on 'Mechanical
methods of thromboprophylaxis'.)

● For ambulatory outpatients, anticoagulation has been reserved for those who have had a prior
VTE and those with high-risk features. Two randomized trials evaluated the role of the direct
oral anticoagulants (DOACs) apixaban and rivaroxaban for primary prevention of VTE in
individuals with cancer and showed that these agents can significantly reduce the incidence of
VTE in high-risk patients. These trials are discussed below. (See 'Outpatients (VTE
prophylaxis)' below.)

● Management of anticoagulation in individuals who have concomitant thrombocytopenia is


discussed separately. (See "Anticoagulation in individuals with thrombocytopenia".)

In contrast to primary prevention, anticoagulation for VTE treatment and secondary prevention is
usually warranted, as discussed in detail separately. (See "Anticoagulation therapy for venous
thromboembolism (lower extremity venous thrombosis and pulmonary embolism) in adult patients
with malignancy" and "Treatment and prevention of venous thromboembolism in patients with brain
tumors".)

A number of studies have evaluated the use of statins to decrease the risk of VTE in medical
patients (eg, healthy adults, individuals with atherosclerosis), with mixed results. The effect of
statins on reduction of VTE risk in patients with cancer was evaluated in a retrospective, case-
control study of 740 consecutive patients with a diagnosis of a solid tumor followed for an average
of 10.2 months (range: 2 to 41 months) [44]. Multivariate analysis indicated that statin use was
associated with a significant reduction in the risk of VTE (OR 0.33; 95% CI 0.18-0.59). Routine use
of statins to prevent VTE is premature, pending further data from prospective trials. (See
"Prevention of venous thromboembolic disease in acutely ill hospitalized medical adults", section
on 'Effect of statin or aspirin on risk'.)

Inpatients (VTE prophylaxis)

Hospitalized medical patients — Patients hospitalized with an acute medical illness are at
high risk for the development of VTE that is further increased by the presence of malignancy [45-
47]. Anticoagulant prophylaxis has been shown to reduce the risk of VTE in medical patients, but
an effect on mortality has not been demonstrated. (See "Prevention of venous thromboembolic
disease in acutely ill hospitalized medical adults".)

The efficacy of thromboprophylaxis in the subset of hospitalized medical patients with cancer was
evaluated in a systematic review of randomized trials that compared anticoagulation (LMW heparin
or fondaparinux) with no anticoagulation [42]. For the 307 patients in these trials with cancer, there
was not a significantly reduced risk of VTE, and the pooled relative risk with anticoagulation was

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0.91 (95% CI 0.21-4.0). However, this was a relatively small cohort in a subset analysis. It is
possible that hospitalized patients with active cancer require higher anticoagulant doses with these
agents than non-cancer patients to provide a similar reduction in VTE rates.

Our general practice is as follows:

● For hospitalized patients with cancer and reduced mobility, we suggest pharmacologic
thromboprophylaxis using an anticoagulant rather than mechanical prophylaxis or no
anticoagulation, as long as there are no contraindications (eg, recent surgery, bleeding
diathesis, platelet count <50,000/microL) [48-50]. (See 'Contraindications to anticoagulation'
below.)

This is based on extrapolation from studies of hospitalized medical patients in the general
population, which included patients with cancer. These studies have uniformly found a benefit
from LMW heparin or fondaparinux in VTE prevention for hospitalized patients at high VTE
risk. (See "Prevention of venous thromboembolic disease in acutely ill hospitalized medical
adults".)

Doses of these agents are presented in the table (table 1).

● Hospitalized cancer patients without immobility may also benefit from pharmacologic
thromboprophylaxis based on their increased VTE risk due to malignancy alone, if there is no
active bleeding or contraindications to anticoagulant use. Individual patient bleeding and
thromboembolic risks may be helpful in determining the appropriateness of anticoagulation in
this setting.

● Mechanical thromboprophylaxis can be used in those who cannot receive anticoagulants due
to increased bleeding risk or other concerns. (See "Prevention of venous thromboembolic
disease in acutely ill hospitalized medical adults", section on 'Mechanical methods of
thromboprophylaxis'.)

● For most patients with cancer admitted for minor procedures or short chemotherapy infusion,
there are insufficient data to support routine thromboprophylaxis.

● Although individuals with acute lymphoblastic leukemia are at especially high risk of VTE
during treatment with L-asparaginase, data are inadequate to support prophylactic
anticoagulation of this population. (See "Overview of the treatment of acute lymphoblastic
leukemia/lymphoma in children and adolescents", section on 'Thrombosis' and
"Thromboembolism in children with cancer", section on 'Primary prevention'.)

Our practice is consistent with guidelines published by the American Society of Clinical Oncology,
the National Comprehensive Cancer Network, and an international consensus group. (See 'Society
guidelines' below.)

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For patients with cancer who are hospitalized with an acute medical illness and require
thromboprophylaxis, we suggest LMW heparin rather than a DOAC due to the lower risk of
bleeding with LMW heparin. This lower risk has been demonstrated in large randomized trials such
as MAGELLAN (rivaroxaban at prophylactic dosing [10 mg daily] versus the LMW heparin
enoxaparin for 35 days in hospitalized patients with an acute medical illness), in which the risk of
bleeding was approximately twofold greater with rivaroxaban (2.8 versus 1.2 percent); 7 percent of
patients in this trial had active cancer [51]. The ADOPT trial (apixaban versus enoxaparin for 30
days in acutely ill medical patients) also found increased bleeding with apixaban compared with
LMW heparin, although bleeding incidence for both groups was <0.5 percent; 3 percent of patients
in this trial had active cancer [52]. As noted above, a meta-analysis of trials comparing LMW
heparin versus placebo in patients with cancer found a trend towards increased risk of major
bleeding that did not reach statistical significance (relative risk, 1.30; 95% CI 0.94-1.79) [53].
Further details regarding these trials are presented separately. (See "Prevention of venous
thromboembolic disease in acutely ill hospitalized medical adults", section on 'Duration of
prophylaxis'.)

Additional aspects of VTE prevention in hospitalized medical patients (eg, dosing, timing of
initiation) are discussed separately. (See "Prevention of venous thromboembolic disease in acutely
ill hospitalized medical adults".)

Surgical patients — Postoperative VTE is more frequent in patients with known cancer than in
the general population, occurring in as many as 40 percent of patients in clinical trials employing
venography for diagnosis [45,54-57]. As a result, individuals with cancer should be considered high
risk for development of postoperative VTE. This increased risk is reflected in the Caprini score for
VTE in surgical patients, which assigns two points for the presence of malignancy (table 2).

● For most patients with cancer undergoing surgery, we recommend perioperative VTE
prophylaxis using an anticoagulant rather than mechanical prophylaxis or no prophylaxis. This
is largely extrapolated from trials that evaluated surgical patients without cancer, for whom the
risk of perioperative VTE and the benefit of prophylactic anticoagulation, for both VTE
prevention and reduction of mortality, are well studied. (See "Prevention of venous
thromboembolic disease in adult nonorthopedic surgical patients".)

● Exceptions include those undergoing minor procedures (eg, central venous catheter
placement), who may not require anticoagulation, and those with a contraindication, who
should receive mechanical thromboprophylaxis. (See 'Contraindications to anticoagulation'
below.)

● Commonly used agents for surgical VTE prophylaxis in patients with cancer include LMW
heparin, unfractionated heparin, and fondaparinux. Decisions among these agents may be
guided by individual patient factors (eg, renal function). (See "Heparin and LMW heparin:
Dosing and adverse effects" and "Fondaparinux: Dosing and adverse effects".)

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Similar efficacy of these agents in perioperative VTE prevention in patients with cancer was
reported in a meta-analysis of 16 randomized trials (12,890 patients) [58]. Similar risks were
seen for the following outcomes with LMW versus unfractionated heparin:

• Mortality (risk ratio [RR] 0.89; 95% CI 0.74-1.08)


• Pulmonary embolism (RR 0.73; 95% CI 0.34-1.54)
• Symptomatic deep vein thrombosis (RR 0.50; 95% CI 0.20-1.28)
• Major bleeding (RR 0.85; 95% CI 0.52-1.37)

Doses of these agents are shown in the table (table 1).

● The optimal duration of postoperative anticoagulation in patients with cancer is unknown, but it
is likely to be longer than that for patients without cancer. We generally initiate anticoagulation
approximately 12 hours postoperatively and continue it for 10 to 14 days. Four weeks may be
reasonable in those undergoing extensive abdominal or pelvic surgery [59]. Some clinicians,
especially in European countries, will initiate prophylactic anticoagulation the day before
surgery rather than postoperatively. (See "Prevention of venous thromboembolic disease in
adult nonorthopedic surgical patients", section on 'Timing of initiation'.)

The benefit of a longer duration of postoperative anticoagulation than typically used for individuals
without cancer was shown in three separate trials that randomized patients undergoing major
cancer surgery to one week versus four weeks of a LMW heparin (1247 patients total) [60-62].
These trials all showed a significant reduction in the incidence of VTE after four weeks of
anticoagulation compared with one week (5 versus 12, 7 versus 16, and 13 versus 10 percent).
None of the trials showed increased bleeding in the prolonged anticoagulation group.

In patients undergoing major general surgery, trials have not been conducted using direct oral
anticoagulants (eg, direct thrombin inhibitors or direct factor Xa inhibitors). Thus, we do not use
these agents as thromboprophylaxis following major general surgical procedures in patients with
cancer. A DOAC may be used for prophylaxis in cancer patients undergoing orthopedic surgery.

Our practice is consistent with guidelines published by the American Society of Clinical Oncology,
the National Comprehensive Cancer Network, and an international consensus group. (See 'Society
guidelines' below.)

Additional aspects of perioperative anticoagulation are discussed separately. (See "Prevention of


venous thromboembolic disease in adult nonorthopedic surgical patients".)

Outpatients (VTE prophylaxis)

VTE risk assessment/Khorana score — Several scores for predicting the risk of VTE in
ambulatory outpatients with cancer have been developed [33,63-71]. Among these, the Khorana
score, introduced in 2008, has been validated in large cohorts of patients with a variety of

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malignancies who are undergoing chemotherapy [63]. We prefer the Khorana score over other
scoring systems for estimating VTE risk. (See 'Whom to anticoagulate' below.)

The Khorana score is calculated by assigning points for clinical parameters available for most
patients (ie, site of primary tumor, hematologic parameters, and body mass index) (calculator 1).
These parameters are summarized in the table (table 3). It was derived in a cohort of 2701 patients
with cancer undergoing chemotherapy and validated in an independent cohort of 1365 patients
[63]. Patients were stratified into three risk groups to predict the development of VTE. The
cumulative incidence of VTE at 2.5 months ranged from 0.3 percent to 6.7 percent in patients with
the fewest and most risk factors, respectively.

Most studies of the Khorana score evaluate the performance of the score over six months of
observation, which often corresponds with the duration of chemotherapy. Evidence for the
predictive value of the score in various cancer populations includes the following:

● The score was evaluated in a meta-analysis that determined VTE risk in nearly 35,000
ambulatory cancer patients who were followed for six months; most were retrospective
analyses that included a number of tumor types [72]. The majority of patients had a Khorana
score of 1 or 2 (64 percent); the score was 0 in 19 percent and 3 or greater in 17 percent. Six-
month VTE risk correlated with the score: those with a score of 0 had a risk of 5 percent; those
with a score of 1 or 2 had a risk of 6.6 percent; and those with a score of 3 or greater had a
risk of 11 percent. Because most of the patients had a score of 1 or 2, this group accounted
for most of the events. The VTE risk for individuals with a score of 2 or greater (the criterion
used in the AVERT and CASSINI trials (see 'Evidence from clinical trials' below)) was 8.9
percent. The authors noted that there is debate about whether this risk of 9 percent justifies
thromboprophylaxis.

● The Khorana score was also validated in an independent study of 1415 patients with
advanced malignancy enrolled in phase I chemotherapy trials, and a modified version of the
score was used in an observational cohort study (the Vienna Cancer and Thrombosis Study)
[73,74]. The modified score included additional high risk tumor types (brain, myeloma, kidney)
and two additional laboratory values (soluble P-selectin and D-dimer levels). In a retrospective
analysis, the cumulative incidence rates of VTE at six months were 1 percent for the lowest
risk group (0 points) and 35 percent for the highest risk group (≥5 points).

Additional studies of individuals with cancer have confirmed a higher incidence of VTE in
those with abnormal coagulation studies, including elevated D-dimer levels, peak thrombin
generation, prothrombin fragment 1+2, tissue factor, and fibrinogen [64,65,75,76].

Whom to anticoagulate

Overview of decision-making — Evidence from randomized trials has demonstrated that


anticoagulation with direct factor Xa inhibitors or LMW heparin can reduce VTE risk in outpatients

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(see 'Evidence from clinical trials' below). At the same time, anticoagulation likely increases the
risk of bleeding. Thus, the decision to use prophylactic anticoagulation is generally individualized
according to the specific thrombotic and bleeding risks for the individual patient, along with the
relative values placed on avoiding thrombosis and avoiding bleeding.

Other considerations include the associated risks and burdens of continuing anticoagulation when
the optimal duration is not well established (table 4).

For most individuals at relatively low risk of VTE (eg, Khorana score <2), we suggest not using
anticoagulation for primary VTE prophylaxis; however, secondary prophylaxis may be considered
for selected patients such as those with a prior history of a major venous thromboembolic event if
they are not chronically maintained on anticoagulation.

We are most likely to suggest anticoagulation for primary VTE prophylaxis in individuals at
especially high VTE risk, as they are likely to have a greater absolute risk reduction. Examples
include the following:

● Individuals with multiple myeloma or non-Hodgkin lymphoma treated with an


immunomodulatory drug (IMiD; eg, thalidomide or lenalidomide)-containing regimen [77].
Arterial events (eg, stroke, myocardial infarction) are also increased in this population. The
need for prophylaxis and the choice of agent depends on the patient's risk stratification. This
issue is discussed in detail separately. (See "Multiple myeloma: Prevention of venous
thromboembolism in patients receiving immunomodulatory drugs (thalidomide, lenalidomide,
and pomalidomide)".)

● Selected ambulatory patients with a Khorana score ≥3, or individuals with a Khorana score of
2 who place a higher value on avoiding VTE than on avoiding bleeding. The Khorana score is
well validated and easy to calculate based on available clinical information (table 3). Many of
these patients will have high-risk malignancies such as pancreatic cancer. (See "Supportive
care of the patient with locally advanced or metastatic exocrine pancreatic cancer", section on
'Venous thromboembolism'.)

● Some individuals with a prior history of unprovoked VTE unrelated to their tumor who are not
already on chronic anticoagulation. Prior VTE is not included in the Khorana score. Decisions
for these patients should be individualized to reflect the relative risks and benefits of
anticoagulation, and the values and preferences of the patient.

When anticoagulation is used in these individuals, a direct factor Xa inhibitor such as apixaban or
rivaroxaban or a LMW heparin may be selected. A prophylactic dose level should be used.
Patients should be aware that their baseline bleeding risk may be higher than the general
population (table 5), and that anticoagulation may further increase this risk, as discussed below.
(See 'Evidence from clinical trials' below.)

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The need for prophylactic anticoagulation around the time of outpatient surgical procedures is
discussed separately. (See "Prevention of venous thromboembolic disease in adult nonorthopedic
surgical patients", section on 'Selecting thromboprophylaxis'.)

Guidelines published by the American Society of Clinical Oncology, the National Comprehensive
Cancer Network, and an international consensus group before the trials with direct factor Xa
inhibitors were available did not recommend routine VTE prophylaxis in ambulatory patients with
cancer, except for those at very high risk of VTE (eg, multiple myeloma receiving thalidomide or
lenalidomide plus chemotherapy or dexamethasone). (See 'Society guidelines' below.)

Evidence from clinical trials — Data on the reduction of VTE risk with anticoagulants in
ambulatory individuals with cancer are available from randomized trials that have compared LMW
heparins with placebo and direct factor Xa inhibitors with placebo. Trials comparing LMW heparin
with a factor Xa inhibitor or different factor Xa inhibitors with each other are not available. Overall,
most trials have shown a reduction of symptomatic VTE with anticoagulation. As expected, the
absolute risk reduction is greatest in those with the highest baseline VTE risk [78].

● Apixaban or rivaroxaban in patients with a Khorana score ≥2 receiving chemotherapy


(AVERT and CASSINI trials) – Two trials published in 2019 addressed the use of a direct
factor Xa inhibitor in patients with a Khorana score ≥2 who were receiving chemotherapy. As
noted above, the Khorana score assigns 2 points for pancreatic and gastric cancers; 1 point
for several other high-risk tumors; and 1 point each for high white blood cell count, platelet
count, hemoglobin, and body mass index (table 3). The baseline risk of VTE correlates with
the score; a score of 2 has been reported to be associated with a risk of VTE of approximately
10 percent over six months and a score of 3 with a risk of 18 percent over six months. (See
'VTE risk assessment/Khorana score' above.)

• The AVERT trial randomly assigned 574 ambulatory individuals with cancer who had
Khorana score ≥2 and were starting chemotherapy to receive the direct factor Xa inhibitor
apixaban at prophylactic dose (2.5 mg twice daily) or placebo for 180 days [79].
Compared with placebo, apixaban resulted in a 6 percent absolute risk reduction in VTE
(from 10.2 percent with placebo to 4.2 percent with apixaban in a modified intention-to-
treat analysis [number needed to treat 17]; hazard ratio [HR] 0.41; 95% CI 0.26-0.65;
adjusted odds ratio [OR] 0.39; 95% CI 0.20-0.76). VTE events included one fatal
pulmonary embolism in the placebo group. Apixaban was also associated with an
increase in major bleeding (3.5 percent, versus 1.8 percent with placebo [number needed
to harm 59]; absolute difference, 1.7 percent; HR 2.0; 95% CI 1.01-3.95). Most of the
bleeding events were gastrointestinal, urinary, or gynecologic, and there was no fatal
bleeding. However the major bleed rate was not significantly higher during the treatment
period (2.1 percent with apixaban and 1.1 percent with placebo, respectively [HR 1.89;
95% CI 0.39-9.24, number needed to harm 100]). Approximately one-fourth to one-fifth of
patients in both arms were receiving an anti-platelet agent and one-fourth had
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gynecologic tumors. There were no other major treatment-related adverse events.


Mortality was 12 percent with apixaban and 10 percent with placebo; most deaths were
associated with cancer progression.

• The CASSINI trial randomly assigned 841 individuals with cancer who had a Khorana
score ≥2 who were starting chemotherapy to receive rivaroxaban (10 mg once daily) or
placebo for 180 days [80]. Unlike the AVERT trial, in CASSINI, all participants underwent
baseline screening with bilateral leg duplex compression ultrasonography. Compared with
placebo, rivaroxaban resulted in a 2.8 percent absolute risk reduction in VTE (from 8.8
percent with placebo to 6 percent with rivaroxaban; HR 0.66; 95% CI 0.40-1.09) in the
intention-to-treat analysis. Many of the thrombotic events, however, occurred when
patients were off anticoagulation. In the pre-specified intervention period analysis, VTE
occurred in 2.6 percent in the rivaroxaban group and 6.4 percent in the placebo group
(HR 0.40; 95% CI 0.20-0.80). Arterial thromboembolism occurred in 1.7 percent of
placebo-treated patients and 1 percent of rivaroxaban-treated patients. Rivaroxaban was
associated with an increase in major bleeding that did not reach statistical significance
(2.0 percent, versus 1 percent with placebo; HR 1.96; 95% CI 0.59-6.49) and a reduction
in mortality that barely reached significance (29.5 versus 23.1 percent; HR 0.75; 95% CI
0.57-0.97). There was one fatal bleeding event in the rivaroxaban group.

Taken together, data from these trials are consistent with the expected baseline risks of VTE
and bleeding in this population and suggest that the absolute difference in VTE risk between
the anticoagulant and placebo groups was 4 to 6 percentage points; the number needed to
treat in the intention-to-treat analysis was 24; and the number needed to harm with major
bleeding was 77 [81]. An editorialist noted some potential concerns with extrapolating these
data to the general population, such as that the score does not take into account the specific
chemotherapy regimen, most common types of cancer (colorectal, breast, prostate) were
underrepresented in these trials, and the proportion of patients who completed the entire
anticoagulant regimen was low, leading to significant equipoise regarding the implications for
practice [81]. The absolute benefit is expected to be greater in those with a Khorana score of 3
rather than 2.

These data contribute to our decision not to use prophylactic anticoagulation in individuals
with a low baseline risk of VTE (Khorana score <2) and to be most likely to recommend
anticoagulation in those with the highest baseline risk, as these individuals are likely to receive
the greatest absolute benefit. (See 'Overview of decision-making' above.)

● LMW heparin in patients with solid tumors – The absolute VTE risk reduction was
summarized in a 2017 Cochrane review of trials involving parenteral anticoagulation in
ambulatory patients with cancer, which found a reduction in symptomatic VTE (relative risk
[RR], 0.56; 95% CI 0.47-0.68) and an increase in major bleeding that did not reach statistical
significance (RR 1.30; 95% CI 0.94-1.79) [53].
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The following trials illustrate typical findings when comparing LMW heparin with placebo in
individuals with cancer who were not preselected for a high baseline VTE risk:

• PROTECHT – The Prophylaxis of Thromboembolism during Chemotherapy


(PROTECHT) trial randomly assigned 1150 patients with metastatic or locally advanced
cancer to the LMW heparin nadroparin versus placebo for VTE prevention [82]. Patients
had lung, breast, gastrointestinal, ovarian, or head and neck cancer; an Eastern
Cooperative Oncology Group (ECOG) performance status of ≤2 (table 6); and were
receiving active chemotherapy. Nadroparin (3800 anti-Xa international units
subcutaneously once daily) or placebo was given for the duration of chemotherapy, up to
a maximum of four months. Compared with placebo, patients receiving nadroparin had a
lower incidence of symptomatic venous and arterial thromboembolic events (3.9 percent
with placebo versus 2.0 percent with nadroparin). The risk of bleeding was similar
between groups (major bleeding, 0 versus 0.7 percent).Thromboembolic rates in the
control group were highest in those with cancers of the lung (8.8 percent) and pancreas
(5.9 percent).

• SAVE-ONCO – The SAVE-ONCO trial randomly assigned 3212 patients with metastatic
or locally advanced solid tumors who were beginning a course of chemotherapy to the
ultra-LMW heparin semuloparin (20 mg once daily) versus placebo during chemotherapy
[34]. Compared with placebo, those receiving semuloparin had a lower risk of
symptomatic VTE (3.4 with placebo versus 1.2 percent with semuloparin; HR 0.36; 95%
CI 0.21-0.60). The incidence of major bleeding was similar (1.1 versus 1.2 percent), as
was clinically relevant non-major bleeding (2.0 versus 2.8 percent). Survival was similar
between the groups at approximately 44 percent. Semuloparin was not approved by the
US Food and Drug Administration, and production was halted.

● LMW heparin in pancreatic cancer – In patients with pancreatic cancer, randomized trials
comparing LMW heparin with placebo (eg, PROSPECT, FRAGEM) have shown greater
reductions in the incidence of VTE than in other solid tumors, without increased bleeding or a
difference in survival. Recommendations for VTE prophylaxis in patients with pancreatic
cancer are presented separately. (See "Supportive care of the patient with locally advanced or
metastatic exocrine pancreatic cancer", section on 'Venous thromboembolism'.)

Central venous catheter — Although the presence of a central venous catheter is a risk factor for
VTE in individuals with cancer, there is no evidence to support the routine use of VTE prophylaxis
to prevent central venous catheter thrombosis. This issue is discussed separately. (See "Catheter-
related upper extremity venous thrombosis", section on 'Thrombosis prevention'.)

Society guidelines — Guidelines for VTE prophylaxis in patients with cancer have been published
by several groups [83-89]. These are mostly consistent with our practice, and with each other, in
recommending VTE prophylaxis in hospitalized medical patients, especially those with an acute

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illness or immobility; perioperative VTE prophylaxis, especially for major abdominal or pelvic
surgery; and no prophylaxis for ambulatory outpatients, with the exception of a high-risk subgroup
that includes patients with multiple myeloma receiving combination therapy that includes a
thalidomide analog, and possibly others (eg, those with advanced pancreatic or lung cancer
receiving chemotherapy, those with Khorana scores ≥3) (table 3).

Three cancer-specific guidelines include the following:

● American Society of Clinical Oncology (ASCO) – Revised guidelines were published in


2013 and reaffirmed in 2014/2015 [48,83]. There is a trend towards expanded use of VTE
prophylaxis compared with previous ASCO guidelines [90]. Our approach includes the
following:

• Stronger recommendation for prophylaxis of hospitalized medical patients with an acute


illness or reduced mobility (but not those admitted for minor procedures or chemotherapy
administration)

• Expansion of the list of scenarios in which VTE prophylaxis should be considered (eg,
those advanced pancreatic or lung cancer receiving chemotherapy, those with prior
history of unprovoked VTE)

• Recommendations for VTE risk assessment and patient education regarding VTE risk

● National Comprehensive Cancer Network (NCCN) – Guidelines were published in 2018


[89]. In addition to individuals for whom we use prophylactic anticoagulation, these guidelines
also suggest considering VTE prophylaxis for those with a Khorana score ≥3 (table 3) who put
a higher value on avoiding VTE than on the increased risk of bleeding associated with
anticoagulation.

● International consensus working group – Guidelines were published in 2013 [84]. In


addition to the individuals for whom we use prophylactic anticoagulation, this guideline also
recommends prophylactic anticoagulation for those with acute lymphoblastic leukemia
receiving L-asparaginase.

VTE TREATMENT AND SECONDARY PREVENTION

The use of anticoagulation for VTE treatment and secondary VTE prevention (ie, prevention of
VTE recurrence) in patients with cancer is discussed in detail separately. (See "Anticoagulation
therapy for venous thromboembolism (lower extremity venous thrombosis and pulmonary
embolism) in adult patients with malignancy".)

CONTRAINDICATIONS TO ANTICOAGULATION
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Patients with malignancy may have tumor-specific factors that lead to an unacceptably high
bleeding risk with anticoagulation (table 7). These include active major bleeding, severe
uncompensated coagulopathy, thrombocytopenia or severe platelet dysfunction, uncontrolled
hypertension, and recent or planned surgery or invasive procedure (eg, lumbar puncture, spinal or
epidural anesthesia) [48].

Possible relative contraindications to anticoagulation include intracranial or spinal lesions, active


gastrointestinal ulceration, or recent severe bleeding (table 7). The presence of an intracranial or
spinal tumor alone is not an absolute contraindication to anticoagulation, although many experts
would avoid anticoagulation in the presence of central nervous system tumors at high risk of
bleeding (eg, associated with a platelet count <50,000/microL or in patients expected develop this
degree of thrombocytopenia from cancer therapy) [91,92]. The approach to anticoagulation in
individuals with platelet counts <50,000/microL may include temporarily holding anticoagulation or
using a lower dose of the anticoagulant, as discussed separately. (See "Anticoagulation in
individuals with thrombocytopenia".)

Mechanical methods may be used for individuals who require thromboprophylaxis but cannot
receive an anticoagulant. (See "Prevention of venous thromboembolic disease in acutely ill
hospitalized medical adults", section on 'Mechanical methods of thromboprophylaxis'.)

EFFECTS ON SURVIVAL

In addition to preventing VTE, some people wonder if anticoagulation could potentially prolong
survival through another mechanism (eg, through a direct anti-tumor effect). Available data are
mixed. However, evidence from clinical trials does not support the use of anticoagulation to
prolong survival through a direct anti-tumor effect in the absence of another indication:

● LMW heparin – Several meta-analyses of randomized trials comparing low molecular weight
(LMW) heparin with placebo have not found any improvement (or reduction) in survival
[53,93,94].

● Oral anticoagulants – Cochrane reviews from 2017 and 2014 (mostly evaluating warfarin
versus no warfarin) and randomized trials from 2019 comparing direct factor Xa inhibitors
versus placebo have not found any survival benefit with oral anticoagulants [79,95,96]. A
study that evaluated DOACs in an animal model did not show any effect on tumor growth [97].

In the absence of consistent data indicating a survival benefit, we agree with guidelines that
recommended against the use of anticoagulants for the purpose of improving survival in patients
with cancer who do not have VTE. (See 'Society guidelines' above.)

SOCIETY GUIDELINE LINKS


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Links to society and government-sponsored guidelines from selected countries and regions around
the world are provided separately. (See "Society guideline links: Anticoagulation".)

SUMMARY AND RECOMMENDATIONS

● Clinical venous thromboembolism (VTE) occurs in as many as 10 percent of patients with


cancer and is associated with increased mortality. Risk factors include hospitalization, surgery,
and with tumor-, patient-, and therapy-specific factors. (See 'Incidence and risk factors' above
and 'Association between VTE and mortality' above.)

● Inpatients – For most hospitalized medical patients with cancer and reduced mobility who do
not have an increased bleeding risk, we suggest pharmacologic thromboprophylaxis rather
than no anticoagulation (Grade 2B). (See 'Hospitalized medical patients' above.)

For patients with cancer undergoing surgery, we recommend perioperative VTE prophylaxis
using an anticoagulant rather than no prophylaxis (Grade 1B). (See 'Surgical patients' above
and "Prevention of venous thromboembolic disease in adult nonorthopedic surgical patients".)

Commonly used agents for VTE prophylaxis in hospitalized patients with cancer include low
molecular weight (LMW) heparin, unfractionated heparin, and fondaparinux; the choice among
these agents depends on patient-specific factors. Doses of these agents are shown in the
table (table 1). Warfarin generally is not used for brief-duration anticoagulation due to its
delayed onset of antithrombotic action and requirement for dose adjustment. We generally do
not use the direct oral anticoagulants (DOACs; eg, direct thrombin inhibitors or direct factor Xa
inhibitors), as they are associated with a greater risk of bleeding than heparins. An exception
is patients who are already receiving these agents when admitted to the hospital.

When indicated, anticoagulation for VTE prophylaxis is generally considered safe if the
platelet count is ≥50,000/microL, its use is individualized for those with counts between 25,000
and 50,000/microL, and it is generally not used for those with platelet counts <25,000/microL,
as discussed in more detail separately. (See "Anticoagulation in individuals with
thrombocytopenia".)

● Outpatients – Evidence regarding the role of anticoagulation for primary prevention of VTE in
outpatients with cancer is evolving. Anticoagulation has consistently been demonstrated to
reduce VTE risk in randomized trials, with the absolute risk reduction dependent on the
baseline risk of VTE. Bleeding risk is increased by anticoagulation. Thus, the decision to use
prophylactic anticoagulation is individualized according to the patient's baseline risks of
thrombosis and bleeding and the relative value they place on avoiding these risks. VTE risk
assessment can be quantified using the Khorana score (calculator 1); parameters and
associated VTE risk are summarized in the table (table 3). (See 'Outpatients (VTE
prophylaxis)' above.)
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For most individuals with cancer, we suggest not using anticoagulation for primary prophylaxis
(Grade 2B).

However, individuals with a higher baseline risk (eg, Khorana score ≥3 or Khorana score ≥2
with a high value placed on avoiding VTE) may reasonably choose anticoagulation, using
either a direct factor Xa inhibitor such as apixaban or rivaroxaban or a LMW heparin, at
prophylactic doses. They should be aware that their baseline bleeding risk may also be
increased and anticoagulation may further increase this risk (table 5). Other caveats of which
to be aware are summarized in the table (table 4).

Management of selected populations with a very high baseline risk of VTE (eg, multiple
myeloma receiving an immunomodulatory drug, pancreatic cancer, prior VTE) is discussed in
detail separately. (See "Multiple myeloma: Prevention of venous thromboembolism in patients
receiving immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide)", section
on 'Venous thromboembolism prophylaxis' and "Supportive care of the patient with locally
advanced or metastatic exocrine pancreatic cancer", section on 'Prophylaxis'.)

● VTE treatment and secondary VTE prevention in patients with cancer (ie, prevention of
recurrence in individuals who have already had a VTE event) are discussed separately. (See
"Anticoagulation therapy for venous thromboembolism (lower extremity venous thrombosis
and pulmonary embolism) in adult patients with malignancy".)

● The use of anticoagulation to prolong survival in the absence of another indication is not
supported by available data. (See 'Effects on survival' above.)

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95. Akl EA, Kahale L, Terrenato I, et al. Oral anticoagulation in patients with cancer who have no
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Rev 2017; 12:CD006466.

97. Buijs JT, Laghmani EH, van den Akker RFP, et al. The direct oral anticoagulants rivaroxaban
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GRAPHICS

Options for parenteral venous thromboembolism (VTE) prophylaxis in patients


with cancer

Surgical patients (postoperative


Hospitalized medical patients
dosing*)

Unfractionated heparin

Unfractionated 5000 units once every 8 to 12 hours 5000 units once every 8 to 12 hours
heparin beginning 6 to 24 hours postoperatively

Low molecular weight (LMW) heparin

Dalteparin 5000 units once daily 5000 units once daily beginning 12 to 24
hours postoperatively

Enoxaparin 40 mg once daily 40 mg once daily beginning 12 to 24 hours


postoperatively

Nadroparin ¶ 3800 anti-Xa units once daily 3800 anti-Xa units once daily beginning 12
to 24 hours postoperatively

Tinzaparin ¶ 3500 anti-Xa units once daily 3500 anti-Xa units once daily beginning 12
to 24 hours postoperatively

Fondaparinux

Fondaparinux 2.5 mg once daily 2.5 mg once daily beginning 6 to 8 hours


postoperatively or beginning on the morning
of the day after surgery

These doses apply to VTE prophylaxis (not treatment) and are appropriate for patients with active cancer.
Administration is by subcutaneous injection for all of the agents listed. Dose adjustments may be required for renal
insufficiency or for obesity. For surgical patients, some surgeons will start prophylaxis preoperatively, depending
on the specific procedure, bleeding risk, and thrombosis risk. Refer to UpToDate topics on VTE prevention in
patients with cancer and VTE treatment in patients with cancer for further information including use of parenteral
as well as oral anticoagulants.

VTE: venous thromboembolism.


* Preoperative dosing may be appropriate in selected settings as long as there is no concern about bleeding with
anticoagulation (eg, due to neuraxial anesthesia or spine surgery). Refer to UpToDate for details of anticoagulation
management in individuals undergoing neuraxial anesthesia or procedures involving the central nervous system.
¶ Not available in the United States.

Adapted from: Lyman GH, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in
patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31:2189.

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Modified Caprini risk assessment model for VTE in general surgical patients

Risk score

1 point 2 points 3 points 5 points

Age 41 to 60 years Age 61 to 74 years Age ≥75 years Stroke (<1 month)

Minor surgery Arthroscopic surgery History of VTE Elective arthroplasty

BMI >25 kg/m 2 Major open surgery (>45 Family history of VTE Hip, pelvis, or leg fracture
minutes)

Swollen legs Laparoscopic surgery (>45 Factor V Leiden Acute spinal cord injury
minutes) (<1 month)

Varicose veins Malignancy Prothrombin 20210A

Pregnancy or postpartum Confined to bed (>72 Lupus anticoagulant


hours)

History of unexplained or Immobilizing plaster cast Anticardiolipin antibodies


recurrent spontaneous
abortion

Oral contraceptives or Central venous access Elevated serum


hormone replacement homocysteine

Sepsis (<1 month) Heparin-induced


thrombocytopenia

Serious lung disease, Other congenital or


including pneumonia (<1 acquired thrombophilia
month)

Abnormal pulmonary
function

Acute myocardial infarction

Congestive heart failure


(<1 month)

History of inflammatory
bowel disease

Medical patient at bed rest

Interpretation

Estimated VTE risk in


the absence of
Surgical risk category* Score pharmacologic or
mechanical prophylaxis
(percent)

Very low (see text for 0 <0.5


definition)

Low 1 to 2 1.5

Moderate 3 to 4 3.0

High ≥5 6.0

VTE: venous thromboembolism; BMI: body mass index.


* This table is applicable only to general, abdominal-pelvic, bariatric, vascular, and plastic and reconstructive surgery. See
text for other types of surgery (eg, cancer surgery).

From: Gould MK, Garcia DA, Wren SM, et al. Prevention of VTE in nonorthopedic surgical patients: antithrombotic therapy
and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practical guidelines.
Chest 2012; 141:e227S. Copyright © 2012. Reproduced with permission from the American College of Chest Physicians.

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Khorana score for estimating venous thromboembolism risk in patients with


cancer

Khorana score

Risk factor Points

Site of primary tumor


Very high risk (stomach, pancreas) 2
High risk (lung, lymphoma, gynecologic, 1
bladder, testicular)
All other sites 0

Pre-chemotherapy platelet count 1


≥350,000/microL

Hemoglobin level <10 g/dL or use of ESAs 1

Pre-chemotherapy WBC >11,000/microL 1

BMI ≥35 kg/m 2 1

Incidence of VTE based on Khorana score

Khorana score Derivation cohort [1] Validation cohort [1] Independent Patients in phase I
points VTE risk after 2.5 VTE risk after 2.5 cohort [2] trials [3]
months months VTE risk after 6 VTE risk after 2
months months

0 (low) 0.8% 0.3% 1.5% 1.5%

1 to 2 1.8% 2% 3.8% (1 point); 4.8%


(intermediate) 9.6% (2 points)

≥3 (high) 7.1% 6.7% 17.7% 12.9%

The Khorana score was developed from a cohort of 2701 patients with cancer receiving a first course of
chemotherapy to predict the cumulative incidence of VTE at 2.5 months [1]. The score was validated in a cohort of
1365 patients, most of whom (91%) had an ECOG performance status of 0 or 1. The score was tested
independently in 819 patients with newly diagnosed cancer or cancer progression who had not received
chemotherapy within the preceding 3 months to predict the cumulative incidence of VTE at 6 months [2], and in
1415 patients enrolled in phase I clinical trials followed for a median of 2 months [3].

ESAs: erythropoiesis-stimulating agents; WBC: white blood cell; BMI: body mass index; VTE: venous thromboembolism;
ECOG: Eastern Cooperative Oncology Group.

References:
1. Khorana AA, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-
associated thrombosis. Blood 2008; 111:4902.
2. Ay C, Dunkler D, Marosi C, et al. Prediction of venous thromboembolism in cancer patients. Blood 2010; 116:5377.
3. Mandala M, Clerici M, Corradino I, et al. Incidence, risk factors and clinical implications of venous thromboembolism
in cancer patients treated within the context of phase I studies: the 'SENDO experience'. Ann Oncol 2012; 23:1416.

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Caveats for primary VTE prophylaxis in ambulatory cancer patients

Patients and clinicians should be aware of (and able to accommodate) the following
concerns:
Increased risk of bleeding:
Higher baseline bleeding risk in most cancer patients
Increased risk of gastrointestinal bleeding with gastrointestinal tumors
Increased risk of gynecologic bleeding with gynecologic tumors
Increased risk of intracerebral bleeding with brain tumors or brain metastases
Concomitant medications may further increase bleeding risk (eg, aspirin, NSAIDs)

Burdens of therapy:
Need to remember an additional daily or twice-daily medication
Cost may be prohibitive for some individuals
Individuals may need assistance with administration if LMW heparin is chosen
Bleeding complications may interfere with chemotherapy cycles

Possible need for temporary interruption of anticoagulation:


For thrombocytopenia (platelet count <50,000/microL) associated with myelosuppressive chemotherapy
For invasive procedures such as cancer surgery, stent placement, or central venous access device
placement

Unknowns about benefit:


Some features of the Khorana score change over time (platelet count, hemoglobin, WBC count)
Risk reduction may depend on tumor type and other factors
Optimal duration of therapy is not known
Optimal dosing of anticoagulants is unknown in individuals with very high BMI (eg, >40 kg/m 2)

This table does not apply to selected populations for whom anticoagulation is warranted, such as those undergoing
surgical procedures with high VTE risk or those with multiple myeloma receiving an immunomodulatory drug and
high-dose glucocorticoids. Some individuals may reasonably choose primary prophylaxis with a LMW heparin or
with a direct factor Xa inhibitor if they have a high risk of VTE. Examples include:
Khorana score ≥3
Khorana score of 2 with a high value placed on avoiding VTE
Prior VTE not currently receiving anticoagulation
Severe immobility
Tools for estimating VTE risk are imprecise, but the Khorana score may be used; pancreatic cancer and gastric
cancer give a Khorana score of at least 2.

VTE: venous thromboembolism; NSAID: nonsteroidal antiinflammatory drug; LMW: low molecular weight; WBC: white
blood cell; BMI: body mass index.

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Risk factors for bleeding with anticoagulation

Risk factor Odds ratio for bleeding*

Modifiable risk factors

Active peptic ulcer disease 4

Bleeding episode within the previous 3 months 4

Platelet count <50,000/microL 4

ICU or CCU 2.5

Renal insufficiency (eGFR <30; 30 to 59; or ≥60 mL/min/m 2) 2; 1.5; 1

Hepatic insufficiency (INR >1.5) 2

Active cancer 2

Rheumatic disease 2

Central venous catheter 2

Fixed risk factors

Male sex 1.5

Older age (≥85; 40 to 80; or <40 years) 3; 2; 1

Non-white race (Asian, Hispanic, or African descent) 4; 2; 2

These risk factors should be regarded as estimates; it is unclear how the estimated ratios would combine in an
individual patient. Refer to UpToDate for details.

ICU: intensive care unit; CCU: coronary care unit; eGFR: estimated glomerular filtration rate; INR: international
normalized ratio.
* Numbers are rounded to the nearest 0.5.

Adapted from:
1. Decousus H, Tapson VF, Bergmann JF, et al. Factors at admission associated with bleeding risk in medical patients:
findings from the IMPROVE investigators. Chest 2011; 139:69.
2. Schünemann HJ, Cushman M, Burnett AE, et al. American Society of Hematology 2018 guidelines for management
of venous thromboembolism: prophylaxis for hospitalized and nonhospitalized medical patients. Blood Adv 2018;
2:3198.

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Eastern Cooperative Oncology Group (ECOG, Zubrod, World Health Organization)


performance scale

Performance
Definition
status
0 Fully active; no performance restrictions.

1 Strenuous physical activity restricted; fully ambulatory and able to carry out light work.

2 Capable of all self-care but unable to carry out any work activities. Up and about >50% of
waking hours.

3 Capable of only limited self-care; confined to bed or chair >50% of waking hours.

4 Completely disabled; cannot carry out any self-care; totally confined to bed or chair.

Adapted from: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative Oncology
Group. Am J Clin Oncol 1982; 5:649.

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Possible contraindications to anticoagulation

Possible
Factors to consider
contraindication

Active, clinically significant Site and degree of bleeding (eg, nosebleeds and menses generally are not a
bleeding contraindication; active intracerebral bleeding is almost always an
absolute contraindication); interval since bleeding stopped

Severe bleeding diathesis Nature, severity, and reversibility of bleeding diathesis

Severe thrombocytopenia Absolute platelet count, platelet count trend, and platelet function (eg, some
(platelet count individuals with ITP and a platelet count in the range of 30,000 to 50,000 may
<50,000/microL) tolerate anticoagulation if needed)

Major trauma Site and extent of trauma, time interval since event (eg, for a patient with a
mechanical heart valve it may be appropriate to anticoagulate sooner after trauma
than a patient with a lesser indication)

Invasive procedure or Type of procedure and associated bleeding risk, interval between procedure and
obstetric delivery (recent, anticoagulation
emergency, or planned)

Previous intracranial Time interval since hemorrhage and underlying cause (eg, trauma or uncontrolled
hemorrhage hypertension)

Intracranial or spinal tumor Site and type of tumor, other comorbidities

Neuraxial anesthesia Interval since spinal/epidural puncture or catheter removal, other alternatives for
anesthesia. Traumatic procedures are more concerning.

Severe, uncontrolled Absolute blood pressure and blood pressure trend


hypertension

This list does not take the place of clinical judgment in deciding whether or not to administer an anticoagulant. In
any patient, the risk of bleeding from an anticoagulant must be weighed against the risk of thrombosis and its
consequences. The greater the thromboembolic risk, the greater the tolerance for the possibility of bleeding and
for shortening the time interval between an episode of bleeding and anticoagulant initiation. Refer to UpToDate
topics on the specific indication for the anticoagulant and the specific possible contraindication for discussions of
these risks.

ITP: immune thrombocytopenia.

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Contributor
Disclosures
Kenneth
A
Bauer,
MD Consultant/Advisory Boards: Janssen Pharmaceuticals [Anticoagulation
(Rivaroxaban)]. Lawrence
LK
Leung,
MD Nothing to disclose Jennifer
S
Tirnauer,
MD Nothing to disclose

Contributor disclosures are reviewed for conflicts of interest by the editorial group. When found, these are
addressed by vetting through a multi-level review process, and through requirements for references to be
provided to support the content. Appropriately referenced content is required of all authors and must
conform to UpToDate standards of evidence.

Conflict of interest policy

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