Managing recurrent and refractory venous thromboembolism (VTE) in patients with cancer presents unique challenges. This review outlines the complexities and therapeutic strategies for recurrent VTE in cancer patients, which includes distinguishing thrombus acuity, differentiating between tumor and bland thrombi, and evaluating potential contributing factors including anticoagulant adherence, extrinsic tumor compression, drug interactions, and anticoagulant-specific considerations such as heparin-induced thrombocytopenia or antithrombin deficiency. Different anticoagulation strategies are discussed, including the administration of escalated-dose low molecular weight heparin (LMWH) as well as the indications and rationale for switching between direct oral anticoagulants or LMWH.

1.
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
.
2.
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
.
3.
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
.
4.
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
.
5.
Barca-Hernando
M
,
Ortega-Rivera
R
,
Lopez-Ruz
S
, et al.
Prognostic significance of incidental deep vein thrombosis in patients with cancer presenting with incidental pulmonary embolism
.
Cancers (Basel)
.
2020
;
12
(
8
):
2267
.
6.
Qdaisat
A
,
Wechsler
AH
,
Cruz Carreras
MT
, et al.
Concomitant deep vein thrombosis in cancer patients with unsuspected pulmonary embolism
.
Cancers (Basel)
.
2022
;
14
(
18
):
4510
.
7.
Karande
GY
,
Hedgire
SS
,
Sanchez
Y
, et al.
Advanced imaging in acute and chronic deep vein thrombosis
.
Cardiovasc Diagn Ther
.
2016
;
6
(
6
):
493
-
507
.
8.
Needleman
L
,
Cronan
JJ
,
Lilly
MP
, et al.
Ultrasound for lower extremity deep venous thrombosis: multidisciplinary recommendations from the Society of Radiologists in Ultrasound consensus conference
.
Circulation
.
2018
;
137
(
14
):
1505
-
1515
.
9.
Prandoni
P
,
Lensing
AW
,
Prins
MH
, et al.
Residual venous thrombosis as a predictive factor of recurrent venous thromboembolism
.
Ann Intern Med
.
2002
;
137
(
12
):
955
-
960
.
10.
Tan
M
,
Mol
GC
,
van Rooden
CJ
, et al.
Magnetic resonance direct thrombus imaging differentiates acute recurrent ipsilateral deep vein thrombosis from residual thrombosis
.
Blood
.
2014
;
124
(
4
):
623
-
627
.
11.
van Dam
LF
,
Dronkers
CEA
,
Gautam
G
, et al.
;
Theia Study Group
.
Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis
.
Blood
.
2020
;
135
(
16
):
1377
-
1385
.
12.
de Jong
CMM
,
Kroft
LJM
,
van Mens
TE
,
Huisman
MV
,
Stöger
JL
,
Klok
FA
.
Modern imaging of acute pulmonary embolism
.
Thromb Res
.
2024
;
238
:
105
-
116
.
13.
van Dam
LF
,
Dronkers
CEA
,
Gautam
G
, et al.
;
Theia Study Group
.
Magnetic resonance imaging for diagnosis of recurrent ipsilateral deep vein thrombosis
.
Blood
.
2020
;
135
(
16
):
1377
-
1385
.
14.
Kaptein
FHJ
,
van der Hulle
T
,
Braken
SJE
, et al.
Prevalence, treatment, and prognosis of tumor thrombi in renal cell carcinoma
.
JACC CardioOncol
.
2022
;
4
(
4
):
522
-
531
.
15.
Kaufman
LB
,
Yeh
BM
,
Breiman
RS
,
Joe
BN
,
Qayyum
A
,
Coakley
FV
.
Inferior vena cava filling defects on CT and MRI
.
AJR Am J Roentgenol
.
2005
;
185
(
3
):
717
-
726
.
16.
He
X
,
Anthony
DC
,
Catoni
Z
,
Cao
W.
Pulmonary tumor embolism: a retrospective study over a 30-year period
.
PLoS One
.
2021
;
16
(
8
):
e0255917
.
17.
Rana
MK
,
Rahman
O
,
O'Brien
A.
Primary pulmonary angiosarcoma
.
BMJ Case Rep
.
2021
;
14
(
11
).
18.
Sarswat
S
,
Khan
D
,
Sagar
S
,
Kumar
R.
Role of 18 F-FDG PET/CT in the diagnosis of benign vs. malignant tumor thrombus
.
Nucl Med Commun
.
2023
;
44
(
8
):
726
-
731
.
19.
Pei
X
,
Lu
M
,
Liu
Z
, et al.
The value of enhanced multiparameteric MRI diagnostic model for preoperatively predicting surgical methods of inferior vena cava in patients with renal tumors and inferior vena cava tumor thrombus
.
BMC Med Imaging
.
2023
;
23
(
1
):
86
.
20.
Hutchinson
R
,
Rew
C
,
Chen
G
, et al.
The adverse survival implications of bland thrombus in renal cell carcinoma with venous tumor thrombus
.
Urology
.
2018
;
115
:
119
-
124
.
21.
Aly
AK
,
Moussa
AM
,
Chevallier
O
, et al.
Iliocaval and iliofemoral venous stenting for obstruction secondary to tumor compression
.
CVIR Endovasc
.
2024
;
7
(
1
):
33
.
22.
Pouncey
AL
,
Kahn
T
,
Morris
RI
,
Saha
P
,
Thulasidasan
N
,
Black
SA
.
Risk factors and classification of reintervention following deep venous stenting for acute iliofemoral deep vein thrombosis
.
J Vasc Surg Venous Lymphat Disord
.
2022
;
10
(
5
):
1051
-
1058.e31058e3
.
23.
van der Wall
SJ
,
Klok
FA
,
den Exter
PL
, et al.
Continuation of low-molecular-weight heparin treatment for cancer-related venous thromboembolism: a prospective cohort study in daily clinical practice
.
J Thromb Haemost
.
2017
;
15
(
1
):
74
-
79
.
24.
Schaefer
JK
,
Li
M
,
Wu
Z
, et al.
Anticoagulant medication adherence for cancer-associated thrombosis: a comparison of LMWH to DOACs
.
J Thromb Haemost
.
2021
;
19
(
1
):
212
-
220
.
25.
Owusu
T
,
Derkach
A
,
Burge
M
,
Nemirovsky
D
,
Zwicker
JI
.
Bleeding and thrombosis in patients with cancer and acute venous thromboembolism requiring urgent procedures
.
Blood
.
2023
;
142
(
suppl 1
):
2656
.
26.
Bertoletti
L
,
Ollier
E
,
Duvillard
C
, et al.
Direct oral anticoagulants: current indications and unmet needs in the treatment of venous thromboembolism
.
Pharmacol Res
.
2017
;
118
:
33
-
42
.
27.
Ip
BY
,
Ko
H
,
Wong
GL
, et al.
Thromboembolic risks with concurrent direct oral anticoagulants and antiseizure medications: a population-based analysis
.
CNS Drugs
.
2022
;
36
(
12
):
1313
-
1324
.
28.
Perlman
A
,
Wanounou
M
,
Goldstein
R
,
Choshen Cohen
L
,
Singer
DE
,
Muszkat
M.
Ischemic and thrombotic events associated with concomitant Xa-inhibiting direct oral anticoagulants and antiepileptic drugs: analysis of the FDA Adverse Event Reporting System (FAERS)
.
CNS Drugs
.
2019
;
33
(
12
):
1223
-
1228
.
29.
Acton
EK
,
Hennessy
S
,
Gelfand
MA
, et al.
Direct-acting oral anticoagulants and antiseizure medications for atrial fibrillation and epilepsy: risk of thromboembolic and major bleeding events
.
JAMA Neurol
.
2024
.
30.
Kumar
R
,
Bhandari
S
,
Singh
SRK
,
Malapati
S
,
Cisak
KI
.
Incidence and outcomes of heparin-induced thrombocytopenia in solid malignancy: an analysis of the national inpatient sample database
.
Br J Haematol
.
2020
;
189
(
3
):
543
-
550
.
31.
Croles
FN
,
Lukens
MV
,
Mulder
R
,
de Maat
MPM
,
Mulder
AB
,
Meijer
K.
Monitoring of heparins in antithrombin-deficient patients
.
Thromb Res
.
2019
;
175
:
8
-
12
.
32.
Zwicker
JI
,
Wang
T-F
,
DeAngelo
D-J
, et al.
The prevention and management of asparaginase-related venous thromboembolism in adults: guidance from the SSC on hemostasis and malignancy of the ISTH
.
J Thromb Haemost
.
2020
;
18
(
2
):
278
-
284
.
33.
Dufrost
V
,
Risse
J
,
Zuily
S
,
Wahl
D.
Direct oral anticoagulants use in antiphospholipid syndrome: are these drugs an effective and safe alternative to warfarin? A systematic review of the literature
.
Curr Rheumatol Rep
.
2016
;
18
(
12
):
74
.
34.
Tota
V
,
Dagonnier
M
,
Wery
D
, et al.
Antiphospholipid syndrome-induced ischemic stroke following pembrolizumab: case report and systematic review
.
Lung Cancer
.
2021
;
160
:
59
-
65
.
35.
Gupta
A
,
Shah
U
,
Khine
H
,
Vandergriff
T
,
Froehlich
T.
Antiphospholipid syndrome associated with combined immune checkpoint inhibitor therapy
.
Melanoma Res
.
2017
;
27
(
2
):
171
-
173
.
36.
Capecchi
M
,
Abbattista
M
,
Ciavarella
A
,
Uhr
M
,
Novembrino
C
,
Martinelli
I.
Anticoagulant therapy in patients with antiphospholipid syndrome
.
J Clin Med
.
2022
;
11
(
23
):
6984
.
37.
Baumann Kreuziger
L
,
Onwuemene
O
,
Kolesar
E
,
Crowther
M
,
Lim
W.
Systematic review of anticoagulant treatment of catheter-related thrombosis
.
Thromb Res
.
2015
;
136
(
6
):
1103
-
1109
.
38.
Byon
W
,
Nepal
S
,
Schuster
AE
,
Shenker
A
,
Frost
CE
.
Regional gastrointestinal absorption of apixaban in healthy subjects
.
J Clin Pharmacol
.
2018
;
58
(
7
):
965
-
971
.
39.
Cada
DJ
,
Levien
TL
,
Baker
DE
.
Apixaban
.
Hosp Pharm
.
2013
;
48
(
6
):
494
-
509
.
40.
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
.
41.
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
.
42.
Kubitza
D
,
Becka
M
,
Zuehlsdorf
M
,
Mueck
W.
Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects
.
J Clin Pharmacol
.
2006
;
46
(
5
):
549
-
558
.
43.
Zhang
L
,
Peters
G
,
Haskell
L
,
Patel
P
,
Nandy
P
,
Moore
KT
.
A cross-study analysis evaluating the effects of food on the pharmacokinetics of rivaroxaban in clinical studies
.
J Clin Pharmacol
.
2017
;
57
(
12
):
1607
-
1615
.
44.
Hamulyák
EN
,
Daams
JG
,
Leebeek
FWG
, et al.
A systematic review of antithrombotic treatment of venous thromboembolism in patients with myeloproliferative neoplasms
.
Blood Adv
.
2021
;
5
(
1
):
113
-
121
.
45.
Zwicker
JI
,
Paranagama
D
,
Lessen
DS
,
Colucci
PM
,
Grunwald
MR
.
Hemorrhage in patients with polycythemia vera receiving aspirin with an anticoagulant: a prospective, observational study
.
Haematologica
.
2022
;
107
(
5
):
1106
-
1110
.
46.
Ortel
TL
,
Neumann
I
,
Ageno
W
, et al.
American Society of Hematology 2020 guidelines for management of venous thromboembolism: treatment of deep vein thrombosis and pulmonary embolism
.
Blood Adv
.
2020
;
4
(
19
):
4693
-
4738
.
47.
Carrier
M
,
Le Gal
G
,
Cho
R
,
Tierney
S
,
Rodger
M
,
Lee
AY
.
Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients
.
J Thromb Haemost
.
2009
;
7
(
5
):
760
-
765
.
48.
Ihaddadene
R
,
Le Gal
G
,
Delluc
A
,
Carrier
M.
Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis
.
Thromb Res
.
2014
;
134
(
1
):
93
-
95
.
49.
Schulman
S
,
Zondag
M
,
Linkins
L
, et al.
Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis
.
J Thromb Haemost
.
2015
;
13
(
6
):
1010
-
1018
.
50.
Guan
Z
,
Wang
R
,
Hussain
RH
,
Fredenburgh
JC
,
Jaffer
IH
,
Weitz
JI
.
Rivaroxaban and apixaban are less effective than enoxaparin for the prevention of catheter-induced clotting in vitro
.
J Thromb Haemost
.
2023
;
21
(
1
):
76
-
82
.
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