Abstract

The association between malignancy and thrombosis has been recognized for over a century and a half. Patients with cancer have an elevated risk of both initial and recurrent venous thromboembolism (VTE) compared with patients without cancer owing to cancer- and patient-specific factors. Recurrent VTE is common despite anticoagulation, presenting additional management challenges. Patients with cancer also have an increased risk of bleeding when on anticoagulants compared with patients without cancer. This bleeding risk is heightened by the thrombocytopenia common in patients with hematologic malignancies and those treated with intensive myelosuppressive chemotherapy regimens. Despite the advancements in cancer-directed therapy made over the past 15 years, numerous large studies have confirmed that bleeding and VTE recurrence rates remain high in cancer patients. Balancing the increased and competing risks of clotting and bleeding in these patients can be difficult, because management of cancer-associated thrombosis requires anticoagulation despite known increased risks for bleeding. In the context of challenging illustrative cases, this review will describe management approaches to clinical scenarios in which data are sparse: cancer patients with recurrent VTE despite anticoagulation and cancer patients with a new VTE in the setting of severe thrombocytopenia.

References

References
1.
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
.
2.
Hull
RD
,
Pineo
GF
,
Brant
RF
, et al
;
LITE Trial Investigators
.
Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer
.
Am J Med
.
2006
;
119
(
12
):
1062
-
1072
.
3.
Soff
GA
,
Mones
J
,
Wilkins
C
, et al
.
Rivaroxaban treatment of cancer-associated venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional experience
.
Res Pract Thromb Haemost
.
2019
;
3
(
3
):
349
-
356
.
4.
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
.
5.
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
.
6.
Kraaijpoel
N
,
Di Nisio
M
,
Mulder
FI
, et al
.
Clinical impact of bleeding in cancer-associated venous thromboembolism: results from the Hokusai VTE cancer study
.
Thromb Haemost
.
2018
;
118
(
8
):
1439
-
1449
.
7.
Agnelli
G
,
Becattini
C
,
Bauersachs
R
, et al
;
Caravaggio Study Investigators
.
Apixaban versus dalteparin for the treatment of acute venous thromboembolism in patients with cancer: the Caravaggio study
.
Thromb Haemost
.
2018
;
118
(
9
):
1668
-
1678
.
8.
NCCN. Cancer-Associated Venous Thromboembolic Disease (Version 1.2019); Plymouth Meeting, PA: NCCN; 2019.
9.
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
.
10.
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
.
2019
;
2019
:
JCO1901461
.
11.
Farge
D
,
Frere
C
,
Connors
JM
, et al
;
International Initiative on Thrombosis and Cancer (ITAC) advisory panel
.
2019 International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer [published online ahead of print 3 September 2019]
.
Lancet Oncol
doi:10.1016/S1470-2045(19)30336-5
.
12.
Olson
SR
,
Shatzel
JJ
,
DeLoughery
TG
.
Asymptomatic “breakthrough” thrombosis and anticoagulant “failure”: keep calm and carry on
.
Res Pract Thromb Haemost
.
2019
;
3
(
3
):
498
-
502
.
13.
Riess
H
,
Ay
C
,
Bauersachs
R
, et al
.
Use of direct oral anticoagulants in patients with cancer: practical considerations for the management of patients with nausea or vomiting
.
Oncologist
.
2018
;
23
(
7
):
822
-
839
.
14.
Shaw
JR
,
Douketis
J
,
Le Gal
G
,
Carrier
M
.
Periprocedural interruption of anticoagulation in patients with cancer-associated venous thromboembolism: an analysis of thrombotic and bleeding outcomes
.
J Thromb Haemost
.
2019
;
17
(
7
):
1171
-
1178
.
15.
Prandoni
P
,
Lensing
AW
,
Piccioli
A
, et al
.
Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis
.
Blood
.
2002
;
100
(
10
):
3484
-
3488
.
16.
Netley
J
,
Howard
K
,
Wilson
W
.
Effects of body mass index on the safety and effectiveness of direct oral anticoagulants: a retrospective review
.
J Thromb Thrombolysis
.
2019
;
48
(
3
):
359
-
365
.
17.
Short
NJ
,
Connors
JM
.
New oral anticoagulants and the cancer patient
.
Oncologist
.
2014
;
19
(
1
):
82
-
93
.
18.
van Es
N
,
Di Nisio
M
,
Cesarman
G
, et al
.
Comparison of risk prediction scores for venous thromboembolism in cancer patients: a prospective cohort study
.
Haematologica
.
2017
;
102
(
9
):
1494
-
1501
.
19.
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
.
20.
Khorana
AA
,
Soff
GA
,
Kakkar
AK
, et al
;
CASSINI Investigators
.
Rivaroxaban for thromboprophylaxis in high-risk ambulatory patients with cancer
.
N Engl J Med
.
2019
;
380
(
8
):
720
-
728
.
21.
Wang
TF
,
Zwicker
JI
,
Ay
C
, et al
.
The use of direct oral anticoagulants for primary thromboprophylaxis in ambulatory cancer patients: guidance from the SSC of the ISTH [published online ahead of print 15 July 2019]
.
J Thromb Haemost
.
doi:10.1111/jth.14564
.
22.
Francis
CW
,
Kessler
CM
,
Goldhaber
SZ
, et al
.
Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study
.
J Thromb Haemost
.
2015
;
13
(
6
):
1028
-
1035
.
23.
Sørensen
HT
,
Mellemkjaer
L
,
Olsen
JH
,
Baron
JA
.
Prognosis of cancers associated with venous thromboembolism
.
N Engl J Med
.
2000
;
343
(
25
):
1846
-
1850
.
24.
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
.
25.
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
.
26.
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
.
27.
Beyer-Westendorf
J
,
Werth
S
,
Folprecht
G
,
Weiss
N
.
Trousseau’s syndrome in a patient with adenocarcinoma of unknown primary and therapy-resistant venous thrombosis treated with dabigatran and fondaparinux
.
Br J Clin Pharmacol
.
2011
;
72
(
4
):
715
-
716
.
28.
Al-Samkari
H
,
Connors
JM
.
Dual anticoagulation with fondaparinux and dabigatran for treatment of cancer-associated hypercoagulability
.
Am J Hematol
.
2018
;
93
(
6
):
E156
-
E158
.
29.
Pillai
AR
,
Olujohungbe
A
,
Evans
MR
,
Main
NJ
,
Hunt
BJ
.
The management of recurrent VTE in cancer patients receiving therapeutic anticoagulation: the use of dual anticoagulant therapy combined with an IVC filter
.
Blood Coagul Fibrinolysis
.
2010
;
21
(
8
):
766
-
769
.
30.
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
.
31.
Zer
A
,
Moskovitz
M
,
Hwang
DM
, et al
.
ALK-rearranged non-small-cell lung cancer is associated with a high rate of venous thromboembolism
.
Clin Lung Cancer
.
2017
;
18
(
2
):
156
-
161
.
32.
De Giglio
A
,
Porreca
R
,
Brambilla
M
, et al
.
Fatal acute disseminated intravascular coagulation as presentation of advanced ALK-positive non-small cell lung cancer: does oncogene addiction matter?
Thromb Res
.
2018
;
163
:
51
-
53
.
33.
Yoshida
T
,
Hida
T
,
Yatabe
Y
.
Rapid and dramatic response to alectinib in an anaplastic lymphoma kinase rearranged non-small-cell lung cancer patient who is critically ill
.
Anticancer Drugs
.
2016
;
27
(
6
):
573
-
575
.
34.
Ünlü
B
,
Versteeg
HH
.
Cancer-associated thrombosis: the search for the holy grail continues
.
Res Pract Thromb Haemost
.
2018
;
2
(
4
):
622
-
629
.
35.
Monreal
M
,
Falgá
C
,
Valdés
M
, et al
;
Riete Investigators
.
Fatal pulmonary embolism and fatal bleeding in cancer patients with venous thromboembolism: findings from the RIETE registry
.
J Thromb Haemost
.
2006
;
4
(
9
):
1950
-
1956
.
36.
Mahé
I
,
Chidiac
J
,
Bertoletti
L
, et al
;
RIETE investigators
.
The clinical course of venous thromboembolism may differ according to cancer site
.
Am J Med
.
2017
;
130
(
3
):
337
-
347
.
37.
Blom
JW
,
Doggen
CJ
,
Osanto
S
,
Rosendaal
FR
.
Malignancies, prothrombotic mutations, and the risk of venous thrombosis
.
JAMA
.
2005
;
293
(
6
):
715
-
722
.
38.
Grace
RF
,
Dahlberg
SE
,
Neuberg
D
, et al
.
The frequency and management of asparaginase-related thrombosis in paediatric and adult patients with acute lymphoblastic leukaemia treated on Dana-Farber Cancer Institute consortium protocols
.
Br J Haematol
.
2011
;
152
(
4
):
452
-
459
.
39.
Calder
KK
,
Herbert
M
,
Henderson
SO
.
The mortality of untreated pulmonary embolism in emergency department patients
.
Ann Emerg Med
.
2005
;
45
(
3
):
302
-
310
.
40.
Watson
HG
,
Keeling
DM
,
Laffan
M
,
Tait
RC
,
Makris
M
;
British Committee for Standards in Haematology
.
Guideline on aspects of cancer-related venous thrombosis
.
Br J Haematol
.
2015
;
170
(
5
):
640
-
648
.
41.
Khorana
AA
,
Francis
CW
,
Culakova
E
,
Kuderer
NM
,
Lyman
GH
.
Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy
.
J Thromb Haemost
.
2007
;
5
(
3
):
632
-
634
.
42.
Levitan
N
,
Dowlati
A
,
Remick
SC
, et al
.
Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data
.
Medicine (Baltimore)
.
1999
;
78
(
5
):
285
-
291
.
43.
Kraaijpoel
N
,
Bleker
SM
,
Meyer
G
, et al
;
UPE investigators
.
Treatment and long-term clinical outcomes of incidental pulmonary embolism in patients with cancer: an international prospective cohort study
.
J Clin Oncol
.
2019
;
37
(
20
):
1713
-
1720
.
44.
van der Hulle
T
,
den Exter
PL
,
Planquette
B
, et al
.
Risk of recurrent venous thromboembolism and major hemorrhage in cancer-associated incidental pulmonary embolism among treated and untreated patients: a pooled analysis of 926 patients
.
J Thromb Haemost
.
2016
;
14
(
1
):
105
-
113
.
45.
Verso
M
,
Agnelli
G
,
Barni
S
,
Gasparini
G
,
LaBianca
R
.
A modified Khorana risk assessment score for venous thromboembolism in cancer patients receiving chemotherapy: the Protecht score
.
Intern Emerg Med
.
2012
;
7
(
3
):
291
-
292
.
46.
Samuelson Bannow
BT
,
Walter
RB
,
Gernsheimer
TB
,
Garcia
DA
.
Patients treated for acute VTE during periods of treatment-related thrombocytopenia have high rates of recurrent thrombosis and transfusion-related adverse outcomes
.
J Thromb Thrombolysis
.
2017
;
44
(
4
):
442
-
447
.
47.
Cortelezzi
A
,
Moia
M
,
Falanga
A
, et al
;
CATHEM Study Group
.
Incidence of thrombotic complications in patients with haematological malignancies with central venous catheters: a prospective multicentre study
.
Br J Haematol
.
2005
;
129
(
6
):
811
-
817
.
48.
Di Micco
P
,
Ruiz-Giménez
N
,
Nieto
JA
, et al
;
RIETE investigators
.
Platelet count and outcome in patients with acute venous thromboembolism
.
Thromb Haemost
.
2013
;
110
(
5
):
1025
-
1034
.
49.
Warner
MA
,
Woodrum
D
,
Hanson
A
,
Schroeder
DR
,
Wilson
G
,
Kor
DJ
.
Preprocedural platelet transfusion for patients with thrombocytopenia undergoing interventional radiology procedures is not associated with reduced bleeding complications
.
Transfusion
.
2017
;
57
(
4
):
890
-
898
.
50.
Nguyen
E
,
Caranfa
JT
,
Lyman
GH
, et al
.
Clinical prediction rules for mortality in patients with pulmonary embolism and cancer to guide outpatient management: a meta-analysis
.
J Thromb Haemost
.
2018
;
16
(
2
):
279
-
292
.
51.
Noble
S
,
Banerjee
S
,
Pease
NJ
.
Management of venous thromboembolism in far-advanced cancer: current practice [published online ahead of print 25 June 2019]
.
BMJ Support Palliat Care
.
doi:10.1136/bmjspcare-2019-001804
.
52.
Herishanu
Y
,
Misgav
M
,
Kirgner
I
,
Ben-Tal
O
,
Eldor
A
,
Naparstek
E
.
Enoxaparin can be used safely in patients with severe thrombocytopenia due to intensive chemotherapy regimens
.
Leuk Lymphoma
.
2004
;
45
(
7
):
1407
-
1411
.
53.
Monreal
M
,
Zacharski
L
,
Jiménez
JA
,
Roncales
J
,
Vilaseca
B
.
Fixed-dose low-molecular-weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study
.
J Thromb Haemost
.
2004
;
2
(
8
):
1311
-
1315
.
54.
Mantha
S
,
Miao
Y
,
Wills
J
,
Parameswaran
R
,
Soff
GA
.
Enoxaparin dose reduction for thrombocytopenia in patients with cancer: a quality assessment study
.
J Thromb Thrombolysis
.
2017
;
43
(
4
):
514
-
518
.
55.
Carrier
M
,
Khorana
AA
,
Zwicker
J
,
Noble
S
,
Lee
AY
;
Subcommittee on Haemostasis and Malignancy for the SSC of the ISTH
.
Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH
.
J Thromb Haemost
.
2013
;
11
(
9
):
1760
-
1765
.
56.
Lyman
GH
,
Khorana
AA
,
Kuderer
NM
, et al
;
American Society of Clinical Oncology Clinical Practice
.
Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update
.
J Clin Oncol
.
2013
;
31
(
17
):
2189
-
2204
.
57.
Samuelson Bannow
BT
,
Lee
A
,
Khorana
AA
, et al
.
Management of cancer-associated thrombosis in patients with thrombocytopenia: guidance from the SSC of the ISTH
.
J Thromb Haemost
.
2018
;
16
(
6
):
1246
-
1249
.
58.
Angelini
DE
,
Radivoyevitch
T
,
McCrae
KR
,
Khorana
AA
.
Bleeding incidence and risk factors among cancer patients treated with anticoagulation
.
Am J Hematol
.
2019
;
94
(
7
):
780
-
785
.
59.
Witt
DM
,
Delate
T
,
Garcia
DA
, et al
.
Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding
.
Arch Intern Med
.
2012
;
172
(
19
):
1484
-
1491
.
60.
Tittl
L
,
Endig
S
,
Marten
S
,
Reitter
A
,
Beyer-Westendorf
I
,
Beyer-Westendorf
J
.
Impact of BMI on clinical outcomes of NOAC therapy in daily care: results of the prospective Dresden NOAC Registry (NCT01588119)
.
Int J Cardiol
.
2018
;
262
:
85
-
91
.
61.
Al-Samkari
H
,
Connors
JM
.
The role of direct oral anticoagulants in treatment of cancer-associated thrombosis
.
Cancers (Basel)
.
2018
;
10
(
8
):
E271
.
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