Active malignancy is a known prothrombotic state, first described by Armand Trousseau as thrombophlebitis occurring in a patient with metastatic gastric cancer. The most common presentation of cancer-associated thrombosis (CAT) is venous thromboembolism, inclusive of deep venous thrombosis and pulmonary embolism. With advances in survival of many cancers, the incidence of CAT is increasing, and an estimated 15% to 20% of all patients with cancer will experience venous thromboembolism during their treatment. Consequently, management and prevention strategies for CAT are paramount for comprehensive clinical care of patients with active malignancy. Direct oral anticoagulants, which have fixed drug dosing, few drug-drug interactions, lack of monitoring requirements, and ease of oral administration, have emerged as the preferred option for CAT, with significant clinical trial data supporting their use. Here, we review the current treatment and prevention paradigms for patients with CAT, the specific role of direct oral anticoagulants for CAT, and ongoing challenges in CAT treatment.

1.
Eichinger
S
.
Cancer associated thrombosis: risk factors and outcomes
.
Thromb Res
.
2016
;
140
(
suppl 1
):
S12
-
S17
.
2.
Khorana
AA
,
Francis
CW
,
Culakova
E
,
Kuderer
NM
,
Lyman
GH
.
Frequency, risk factors, and trends for venous thromboembolism among hospitalized cancer patients
.
Cancer
.
2007
;
110
(
10
):
2339
-
2346
.
3.
Lyman
GH
,
Culakova
E
,
Poniewierski
MS
,
Kuderer
NM
.
Morbidity, mortality and costs associated with venous thromboembolism in hospitalized patients with cancer
.
Thromb Res
.
2018
;
164
(
suppl 1
):
S112
-
S118
.
4.
Mulder
FI
,
Horváth-Puhó
E
,
van Es
N
, et al
.
Venous thromboembolism in cancer patients: a population-based cohort study
.
Blood
.
2021
;
137
(
14
):
1959
-
1969
.
5.
Wang
T-F
,
Baumann Kreuziger
L
,
Leader
A
, et al
.
Characteristics and outcomes of patients on concurrent direct oral anticoagulants and targeted anticancer therapies—TacDOAC registry: communication from the ISTH SSC Subcommittee on Hemostasis and Malignancy
.
J Thromb Haemost
.
2021
;
19
(
8
):
2068
-
2081
.
6.
Khorana
AA
,
Dalal
M
,
Lin
J
,
Connolly
GC
.
Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States
.
Cancer
.
2013
;
119
(
3
):
648
-
655
.
7.
Petrelli
F
,
Cabiddu
M
,
Borgonovo
K
,
Barni
S
.
Risk of venous and arterial thromboembolic events associated with anti-EGFR agents: a meta-analysis of randomized clinical trials
.
Ann Oncol
.
2012
;
23
(
7
):
1672
-
1679
.
8.
Sussman
TA
,
Li
H
,
Hobbs
B
,
Funchain
P
,
McCrae
KR
,
Khorana
AA
.
Incidence of thromboembolism in patients with melanoma on immune checkpoint inhibitor therapy and its adverse association with survival
.
J Immunother Cancer
.
2021
;
9
(
1
):
e001719
.
9.
Khorana
AA
,
Dalal
MR
,
Lin
J
,
Connolly
GC
.
Health care costs associated with venous thromboembolism in selected high-risk ambulatory patients with solid tumors undergoing chemotherapy in the United States
.
Clinicoecon Outcomes Res
.
2013
;
5
:
101
-
108
.
10.
Lee
AYY
,
Kamphuisen
PW
,
Meyer
G
, et al
;
CATCH Investigators
.
Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial
.
JAMA
.
2015
;
314
(
7
):
677
-
686
.
11.
Kirkilesis
GI
,
Kakkos
SK
,
Tsolakis
IA
.
Editor's choice—a systematic review and meta-analysis of the efficacy and safety of anticoagulation in the treatment of venous thromboembolism in patients with cancer
.
Eur J Vasc Endovasc Surg
.
2019
;
57
(
5
):
685
-
701
.
12.
Lee
AY
,
Levine
MN
,
Baker
RI
, et al
;
Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators
.
Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer
.
N Engl J Med
.
2003
;
349
(
2
):
146
-
153
.
13.
Khorana
AA
,
McCrae
KR
,
Milentijevic
D
, et al
.
Current practice patterns and patient persistence with anticoagulant treatments for cancer-associated thrombosis
.
Res Pract Thromb Haemost
.
2017
;
1
(
1
):
14
-
22
.
14.
Mohammady
M
,
Janani
L
,
Akbari Sari
A
.
Slow versus fast subcutaneous heparin injections for prevention of bruising and site pain intensity
.
Cochrane Database Syst Rev
.
2017
;
11
(
11
):
CD008077
.
15.
van Es
N
,
Coppens
M
,
Schulman
S
,
Middeldorp
S
,
Büller
HR
.
Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials
.
Blood
.
2014
;
124
(
12
):
1968
-
1975
.
16.
Agnelli
G
,
Buller
HR
,
Cohen
A
, et al
;
AMPLIFY Investigators
.
Oral apixaban for the treatment of acute venous thromboembolism
.
N Engl J Med
.
2013
;
369
(
9
):
799
-
808
.
17.
EINSTEIN Investigators
;
Bauersachs
R
,
Berkowitz
SD
,
Brenner
B
, et al
.
Oral rivaroxaban for symptomatic venous thromboembolism
.
N Engl J Med
.
2010
;
363
(
26
):
2499
-
2510
.
18.
Hokusai-VTE Investigators
;
Büller
HR
,
Décousus
H
,
Grosso
MA
, et al
.
Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism
.
N Engl J Med
.
2013
;
369
(
15
):
1406
-
1415
.
19.
EINSTEIN–PE Investigators
;
Büller
HR
,
Prins
MH
,
Lensin
AW
, et al
.
Oral rivaroxaban for the treatment of symptomatic pulmonary embolism
.
N Engl J Med
.
2012
;
366
(
14
):
1287
-
1297
.
20.
Schulman
S
,
Kakkar
AK
,
Goldhaber
SZ
, et al
;
RE-COVER II Trial Investigators
.
Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis
.
Circulation
.
2014
;
129
(
7
):
764
-
772
.
21.
Schulman
S
,
Kearon
C
,
Kakkar
AK
, et al
;
RE-COVER Study Group
.
Dabigatran versus warfarin in the treatment of acute venous thromboembolism
.
N Engl J Med
.
2009
;
361
(
24
):
2342
-
2352
.
22.
Agnelli
G
,
Becattini
C
,
Meyer
G
, et al
;
Caravaggio Investigators
.
Apixaban for the treatment of venous thromboembolism associated with cancer
.
N Engl J Med
.
2020
;
382
(
17
):
1599
-
1607
.
23.
McBane
RD
, et al
.
Apixaban, dalteparin, in active cancer associated venous thromboembolism, the ADAM VTE trial
.
Blood
.
2018
;
132
:
421
.
24.
Planquette
B
,
Bertoletti
L
,
Charles-Nelson
A
, et al
;
CASTA DIVA Trial Investigators
.
Rivaroxaban vs dalteparin in cancer-associated thromboembolism: a randomized trial
.
Chest
.
2022
;
161
(
3
):
781
-
790
.
25.
Raskob
GE
,
van Es
N
,
Verhamme
P
, et al
;
Hokusai VTE Cancer Investigators
.
Edoxaban for the treatment of cancer-associated venous thromboembolism
.
N Engl J Med
.
2018
;
378
(
7
):
615
-
624
.
26.
Young
AM
,
Marshall
A
,
Thirlwall
J
, et al
.
Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D)
.
J Clin Oncol
.
2018
;
36
(
20
):
2017
-
2023
.
27.
Schrag
D
,
Uno
H
,
Rosovsky
R
, et al
;
CANVAS Investigators
.
Direct oral anticoagulants vs low-molecular-weight heparin and recurrent VTE in patients with cancer: a randomized clinical trial
.
JAMA
.
2023
;
329
(
22
):
1924
-
1933
.
28.
Frere
C
,
Farge
D
,
Schrag
D
,
Prata
PH
,
Connors
JM
.
Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials
.
J Hematol Oncol
.
2022
;
15
(
1
):
69
.
29.
Streiff
MB
,
Milentijevic
D
,
McCrae
K
, et al
.
Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer
.
Am J Hematol
.
2018
;
93
(
5
):
664
-
671
.
30.
Gulati
S
,
Eckman
MH
.
Anticoagulant therapy for cancer-associated thrombosis: a cost-effectiveness analysis
.
Ann Intern Med
.
2023
;
176
(
1
):
1
-
9
.
31.
Ageno
W
,
Vedovati
MC
,
Cohen
A
, et al
.
Bleeding with apixaban and dalteparin in patients with cancer-associated venous thromboembolism: results from the Caravaggio study
.
Thromb Haemost
.
2021
;
121
(
5
):
616
-
624
.
32.
Mantha
S
,
Laube
E
,
Miao
Y
, et al
.
Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study
.
J Thromb Thrombolysis
.
2017
;
43
(
2
):
166
-
171
.
33.
Cheung
K-S
,
Leung
W-K
.
Gastrointestinal bleeding in patients on novel oral anticoagulants: risk, prevention and management
.
World J Gastroenterol
.
2017
;
23
(
11
):
1954
-
1963
.
34.
Key
NS
,
Khorana
AA
,
Kuderer
NM
, et al
.
Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update
.
J Clin Oncol
.
2020
;
38
(
5
):
496
-
520
.
35.
Khorana
AA
,
Noble
S
,
Lee
AYY
, et al
.
Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH
.
J Thromb Haemost
.
2018
;
16
(
9
):
1891
-
1894
.
36.
Streiff
MB
,
Holmstrom
B
,
Angelini
D
, et al
.
Cancer-associated venous thromboembolic disease, version 2.2024, NCCN clinical practice guidelines in oncology
.
J Natl Compr Canc Netw
.
2024
;
22
(
7
):
483
-
506
.
37.
Carney
BJ
,
Uhlmann
EJ
,
Puligandla
M
, et al
.
Intracranial hemorrhage with direct oral anticoagulants in patients with brain tumors
.
J Thromb Haemost
.
2019
;
17
(
1
):
72
-
76
.
38.
Vranckx
P
,
Valgimigli
M
,
Heidbuchel
H
.
The significance of drug-drug and drug-food interactions of oral anticoagulation
.
Arrhythm Electrophysiol Rev
.
2018
;
7
(
1
):
55
-
61
.
39.
van Hylckama
Vlieg MAM
,
Nasserinejad
K
,
Visser
C
, et al
.
The risk of recurrent venous thromboembolism after discontinuation of anticoagulant therapy in patients with cancer-associated thrombosis: a systematic review and meta-analysis
.
EClinicalMedicine
.
2023
;
64
:
102194
.
40.
Mahé
I
,
Plaisance
L
,
Chapelle
C
, et al
.
Long-term treatment of cancer-associated thrombosis (CAT) beyond 6 months in the medical practice: USCAT, a 432-patient retrospective non-interventional study
.
Cancers (Basel)
.
2020
;
12
(
8
):
2256
.
41.
Di Nisio
M
,
van Es
N
,
Carrier
M
, et al
.
Extended treatment with edoxaban in cancer patients with venous thromboembolism: a post-hoc analysis of the Hokusai-VTE Cancer study
.
J Thromb Haemost
.
2019
;
17
(
11
):
1866
-
1874
.
42.
McBane
RD II
,
Loprinzi
CL
,
Zemla
T
, et al
;
EVE trial investigators
.
Extending venous thromboembolism secondary prevention with apixaban in cancer patients. The EVE trial
.
J Thromb Haemost
.
2024
;
22
(
6
):
1704
-
1714
.
43.
Mahé
I
,
Carrier
M
,
Mayeur
D
, et al
;
API-CAT Investigators
.
Extended reduced-dose apixaban for cancer-associated venous thromboembolism
.
N Engl J Med
.
2025
;
392
(
14
):
1363
-
1373
.
44.
Agnelli
G
,
Gussoni
G
,
Bianchini
C
, et al
;
PROTECHT Investigators
.
Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study
.
Lancet Oncol
.
2009
;
10
(
10
):
943
-
949
.
45.
Carrier
M
,
Abou-Nassar
K
,
Mallick
R
, et al
;
AVERT Investigators
.
Apixaban to prevent venous thromboembolism in patients with cancer
.
N Engl J Med
.
2019
;
380
(
8
):
711
-
719
.
46.
Khorana
AA
,
Soff
GA
,
Kakkar
AK
, et al
.
Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer
.
N Engl J Med
.
2019
;
380
(
8
):
720
-
728
.
47.
Li
A
,
Carlson
JJ
,
Kuderer
NM
, et al
.
Cost-effectiveness analysis of low-dose direct oral anticoagulant (DOAC) for the prevention of cancer-associated thrombosis in the United States
.
Cancer
.
2020
;
126
(
8
):
1736
-
1748
.
48.
Martin
KA
,
Beyer-Westendorf
J
,
Davidson
BL
,
Huisman
MV
,
Sandset
PM
,
Moll
S
.
Use of direct oral anticoagulants in patients with obesity for treatment and prevention of venous thromboembolism: updated communication from the ISTH SSC Subcommittee on Control of Anticoagulation
.
J Thromb Haemost
.
2021
;
19
(
8
):
1874
-
1882
.
49.
Leong
R
,
Chu
DK
,
Crowther
MA
,
Mithoowani
S
.
Direct oral anticoagulants after bariatric surgery—what is the evidence?
J Thromb Haemost
.
2022
;
20
(
9
):
1988
-
2000
.
50.
Rottenstreich
A
,
Barkai
A
,
Arad
A
,
Raccah
BH
,
Kalish
Y
.
The effect of bariatric surgery on direct-acting oral anticoagulant drug levels
.
Thromb Res
.
2018
;
163
:
190
-
195
.
51.
Hakeam
HA
,
Al-Sanea
N
.
Effect of major gastrointestinal tract surgery on the absorption and efficacy of direct acting oral anticoagulants (DOACs)
.
J Thromb Thrombolysis
.
2017
;
43
(
3
):
343
-
351
.
52.
Grześk
G
,
Rogowicz
D
,
Wołowiec
Ł
, et al
.
The clinical significance of drug-food interactions of direct oral anticoagulants
.
Int J Mol Sci
.
2021
;
22
(
16
):
8531
.
You do not currently have access to this content.