Abstract

Arterial and venous thromboses are the most significant complications in patients with myeloproliferative neoplasms (MPNs), with the primary treatment goal being thrombotic risk reduction. In MPN with no history of thrombosis, primary prevention mainly involves the use of aspirin, and cytoreduction is added in high-risk patients. However, thrombotic complications can unveil an MPN in ∼20% of cases, necessitating the initiation of both antithrombotic therapy for the thrombosis and cytoreductive treatment for the MPN. The duration of anticoagulant therapy after an initial venous thromboembolic event is subject to discussion. Furthermore, the occurrence of a thrombotic complication in patients with a known diagnosis of MPN prompts a reconsideration of both antithrombotic and hematologic management. This review uses case-based discussions to explore the management of thrombotic complications in patients with MPN. It addresses the nature and duration of antithrombotic treatments, as well as the approach to cytoreduction. Special attention is given to the place of direct oral anticoagulants and to the management of patients with MPN with splanchnic vein thrombosis, which is disproportionately common in this group.

1.
Vainchenker
W
,
Kralovics
R
.
Genetic basis and molecular pathophysiology of classical myeloproliferative neoplasms
.
Blood
.
2017
;
129
(
6
):
667
-
679
.
2.
James
C
,
Ugo
V
,
Le Couédic
J-P
, et al
.
A unique clonal JAK2 mutation leading to constitutive signalling causes polycythaemia vera
.
Nature
.
2005
;
434
:
5
.
3.
Kralovics
R
,
Passamonti
F
,
Buser
AS
, et al
.
A gain-of-function mutation of JAK2 in myeloproliferative disorders
.
N Engl J Med
.
2005
;
352
(
17
):
1779
-
1790
.
4.
Baxter
EJ
,
Scott
LM
,
Campbell
PJ
, et al
.
Acquired mutation of the tyrosine kinase JAK2 in human myeloproliferative disorders
.
Lancet
.
2005
;
365
(
9464
):
1054
-
1061
.
5.
Levine
RL
,
Wadleigh
M
,
Cools
J
, et al
.
Activating mutation in the tyrosine kinase JAK2 in polycythemia vera, essential thrombocythemia, and myeloid metaplasia with myelofibrosis
.
Cancer Cell
.
2005
;
7
(
4
):
387
-
397
.
6.
Klampfl
T
,
Gisslinger
H
,
Harutyunyan
AS
, et al
.
Somatic mutations of calreticulin in myeloproliferative neoplasms
.
N Engl J Med
.
2013
;
369
(
25
):
2379
-
2390
.
7.
Nangalia
J
,
Massie
CE
,
Baxter
EJ
, et al
.
Somatic CALR mutations in myeloproliferative neoplasms with nonmutated JAK2
.
N Engl J Med
.
2013
;
369
(
25
):
2391
-
2405
.
8.
Pikman
Y
,
Lee
BH
,
Mercher
T
, et al
.
MPLW515L is a novel somatic activating mutation in myelofibrosis with myeloid metaplasia
.
PLoS Med
.
2006
;
3
(
7
):
e270
.
9.
Hultcrantz
M
,
Björkholm
M
,
Dickman
PW
, et al
.
Risk for arterial and venous thrombosis in patients with myeloproliferative neoplasms: a population-based cohort study
.
Ann Intern Med
.
2018
;
168
(
5
):
317
.
10.
Rungjirajittranon
T
,
Owattanapanich
W
,
Ungprasert
P
,
Siritanaratkul
N
,
Ruchutrakool
T
.
A systematic review and meta-analysis of the prevalence of thrombosis and bleeding at diagnosis of Philadelphia-negative myeloproliferative neoplasms
.
BMC Cancer
.
2019
;
19
(
1
):
184
.
11.
Gerds
AT
,
Mesa
RA
,
Burke
JM
, et al
.
Association between elevated white blood cell counts and thrombotic events in polycythemia vera: analysis from REVEAL
.
Blood
.
2024
;
143
(
16
):
1646
-
1655
.
12.
Hernández-Boluda
J-C
,
Pastor-Galán
I
,
Arellano-Rodrigo
E
, et al
.
Predictors of thrombosis and bleeding in 1613 myelofibrosis patients from the Spanish registry of myelofibrosis
.
Br J Haematol
.
2022
;
199
(
4
):
529
-
538
.
13.
Barbui
T
,
Carobbio
A
,
Cervantes
F
, et al
.
Thrombosis in primary myelofibrosis: incidence and risk factors
.
Blood
.
2010
;
115
(
4
):
778
-
782
.
14.
Buxhofer-Ausch
V
,
Gisslinger
H
,
Thiele
J
, et al
.
Leukocytosis as an important risk factor for arterial thrombosis in WHO-defined early/prefibrotic myelofibrosis: an international study of 264 patients
.
Am J Hematol
.
2012
;
87
(
7
):
669
-
672
.
15.
Elliott
MA
,
Pardanani
A
,
Lasho
TL
,
Schwager
SM
,
Tefferi
A
.
Thrombosis in myelofibrosis: prior thrombosis is the only predictive factor and most venous events are provoked
.
Haematologica
.
2010
;
95
(
10
):
1788
-
1791
.
16.
Carobbio
A
,
Vannucchi
AM
,
Rumi
E
, et al
.
Survival expectation after thrombosis and overt-myelofibrosis in essential thrombocythemia and prefibrotic myelofibrosis: a multistate model approach
.
Blood Cancer J
.
2023
;
13
(
1
):
115
.
17.
Marchioli
R
,
Finazzi
G
,
Landolfi
R
, et al
.
Vascular and neoplastic risk in a large cohort of patients with polycythemia vera
.
J Clin Oncol
.
2005
;
23
(
10
):
2224
-
2232
.
18.
Tefferi
A
,
Rumi
E
,
Finazzi
G
, et al
.
Survival and prognosis among 1545 patients with contemporary polycythemia vera: an international study
.
Leukemia
.
2013
;
27
(
9
):
1874
-
1881
.
19.
Bonicelli
G
,
Abdulkarim
K
,
Mounier
M
, et al
.
Leucocytosis and thrombosis at diagnosis are associated with poor survival in polycythaemia vera: a population-based study of 327 patients
.
Br J Haematol
.
2013
;
160
(
2
):
251
-
254
.
20.
Guy
A
,
Poisson
J
,
James
C
.
Pathogenesis of cardiovascular events in BCR-ABL1-negative myeloproliferative neoplasms
.
Leukemia
.
2021
:
1
-
21
.
21.
Wolach
O
,
Sellar
RS
,
Martinod
K
, et al
.
Increased neutrophil extracellular trap formation promotes thrombosis in myeloproliferative neoplasms
.
Sci Transl Med
.
2018
;
10
(
436
).
22.
Guy
A
,
Garcia
G
,
Gourdou-Latyszenok
V
, et al
.
Platelets and neutrophils cooperate to induce increased neutrophil extracellular trap formation in JAK2V617F myeloproliferative neoplasms
.
J Thromb Haemostasis
.
2024
;
22
(
1
):
172
-
187
.
23.
Farina
M
,
Russo
D
,
Hoffman
R
.
The possible role of mutated endothelial cells in myeloproliferative neoplasms
.
Haematologica
.
2021
;
106
(
11
):
2813
-
2823
.
24.
Smalberg
JH
,
Arends
LR
,
Valla
DC
, et al
.
Myeloproliferative neoplasms in Budd-Chiari syndrome and portal vein thrombosis: a meta-analysis
.
Blood
.
2012
;
120
(
25
):
4921
-
4928
.
25.
Kiladjian
J-J
,
Cassinat
B
.
Myeloproliferative neoplasms and splanchnic vein thrombosis: Contemporary diagnostic and therapeutic strategies
.
Am J Hematol
.
2023
;
98
(
5
):
794
-
800
.
26.
Rumi
E
,
Pietra
D
,
Ferretti
V
, et al
.
JAK2 or CALR mutation status defines subtypes of essential thrombocythemia with substantially different clinical course and outcomes
.
Blood
.
2014
;
123
(
10
):
1544
-
1551
.
27.
Rumi
E
,
Pietra
D
,
Pascutto
C
, et al
.
Clinical effect of driver mutations of JAK2, CALR, or MPL in primary myelofibrosis
.
Blood
.
2014
;
124
(
7
):
1062
-
1069
.
28.
Rotunno
G
,
Mannarelli
C
,
Guglielmelli
P
, et al
.
Impact of calreticulin mutations on clinical and hematological phenotype and outcome in essential thrombocythemia
.
Blood
.
2014
;
123
(
10
):
1552
-
1555
.
29.
Finazzi
MC
,
Carobbio
A
,
Cervantes
F
, et al
.
CALR mutation, MPL mutation and triple negativity identify patients with the lowest vascular risk in primary myelofibrosis
.
Leukemia
.
2015
;
29
(
5
):
1209
-
1210
.
30.
Barbui
T
,
Finazzi
G
,
Carobbio
A
, et al
.
Development and validation of an international prognostic score of thrombosis in world health organization–essential thrombocythemia (IPSET-thrombosis)
.
Blood
.
2012
;
120
(
26
):
5128
-
5133
.
31.
Barbui
T
,
Vannucchi
AM
,
Buxhofer-Ausch
V
, et al
.
Practice-relevant revision of IPSET-thrombosis based on 1019 patients with WHO-defined essential thrombocythemia
.
Blood Cancer J
.
2015
;
5
(
11
):
e369
.
32.
Pasquer
H
,
Daltro de Oliveira
R
,
Vasseur
L
, et al
.
Distinct clinico-molecular arterial and venous thrombosis scores for myeloproliferative neoplasms risk stratification
.
Leukemia
.
2024
;
38
(
2
):
326
-
339
.
33.
Alvarez-Larrán
A
,
Cuevas
B
,
Velez
P
, et al
.
Application of IPSET-thrombosis in 1366 patients prospectively followed from the Spanish registry of essential thrombocythemia
.
Hemasphere
.
2023
;
7
(
8
):
e936
.
34.
Guglielmelli
P
,
Carobbio
A
,
Rumi
E
, et al
.
Validation of the IPSET score for thrombosis in patients with prefibrotic myelofibrosis
.
Blood Cancer J
.
2020
;
10
(
2
):
1
-
8
.
35.
Carobbio
A
,
Finazzi
G
,
Antonioli
E
, et al
.
Thrombocytosis and leukocytosis interaction in vascular complications of essential thrombocythemia
.
Blood
.
2008
;
112
(
8
):
3135
-
3137
.
36.
Campbell
PJ
,
MacLean
C
,
Beer
PA
, et al
.
Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort
.
Blood
.
2012
;
120
(
7
):
1409
-
1411
.
37.
Marchetti
M
,
Vannucchi
AM
,
Griesshammer
M
, et al
.
Appropriate management of polycythaemia vera with cytoreductive drug therapy: European LeukemiaNet 2021 recommendations
.
The Lancet Haematology
.
2022
;
9
(
4
):
e301
-
e311
.
38.
Tefferi
A
.
Primary myelofibrosis: 2023 update on diagnosis, risk-stratification, and management
.
Am J Hematol
.
2023
;
98
(
5
):
801
-
821
.
39.
De Stefano
V
,
Rossi
E
,
Carobbio
A
, et al
.
Hydroxyurea prevents arterial and late venous thrombotic recurrences in patients with myeloproliferative neoplasms but fails in the splanchnic venous district. Pooled analysis of 1500 cases
.
Blood Cancer J
.
2018
;
8
(
11
):
112
.
40.
Bewersdorf
JP
,
Giri
S
,
Wang
R
, et al
.
Interferon alpha therapy in essential thrombocythemia and polycythemia vera - a systematic review and meta-analysis
.
Leukemia
.
2021
;
35
(
6
):
1643
-
1660
.
41.
Gisslinger
H
,
Klade
C
,
Georgiev
P
, et al
.
Ropeginterferon alfa-2b versus standard therapy for polycythaemia vera (PROUD-PV and CONTINUATION-PV): a randomised, non-inferiority, phase 3 trial and its extension study
.
The Lancet Haematology
.
2020
;
7
(
3
):
e196
-
e208
.
42.
Harrison
CN
,
Nangalia
J
,
Boucher
R
, et al
.
Ruxolitinib versus best available therapy for polycythemia vera intolerant or resistant to hydroxycarbamide in a randomized trial
.
J Clin Oncol
.
2023
;
41
(
19
):
3534
-
3544
.
43.
Masciulli
A
,
Ferrari
A
,
Carobbio
A
,
Ghirardi
A
,
Barbui
T
.
Ruxolitinib for the prevention of thrombosis in polycythemia vera: a systematic review and meta-analysis
.
Blood Advances
.
2020
;
4
(
2
):
380
-
386
.
44.
Mora
B
,
Guglielmelli
P
,
Kuykendall
A
, et al
.
Prediction of thrombosis in post-polycythemia vera and post-essential thrombocythemia myelofibrosis: a study on 1258 patients
.
Leukemia
.
2022
;
36
(
10
):
2453
-
2460
.
45.
Harrison
CN
,
Campbell
PJ
,
Buck
G
, et al
.
Hydroxyurea compared with anagrelide in high-risk essential thrombocythemia
.
N Engl J Med
.
2005
;
353
(
1
):
33
-
45
.
46.
Gisslinger
H
,
Gotic
M
,
Holowiecki
J
, et al
.
Anagrelide compared with hydroxyurea in WHO-classified essential thrombocythemia: the ANAHYDRET study, a randomized controlled trial
.
Blood
.
2013
;
121
(
10
):
1720
-
1728
.
47.
Middeldorp
S
,
Nieuwlaat
R
,
Baumann
Kreuziger L
, et al
.
American Society of Hematology 2023 guidelines for management of venous thromboembolism: thrombophilia testing
.
Blood Advances
.
2023
;
7
(
22
):
7101
-
7138
.
48.
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 Advances
.
2020
;
4
(
19
):
4693
-
4738
.
49.
Khan
F
,
Rahman
A
,
Carrier
M
, et al
.
Long term risk of symptomatic recurrent venous thromboembolism after discontinuation of anticoagulant treatment for first unprovoked venous thromboembolism event: systematic review and meta-analysis
.
BMJ
.
2019
;
366
:
l4363
.
50.
Girardi
L
,
Wang
T-F
,
Ageno
W
,
Carrier
M
.
Updates in the incidence, pathogenesis, and management of cancer and venous thromboembolism
.
Arterioscler Thromb Vasc Biol
.
2023
;
43
(
6
):
824
-
831
.
51.
Lyman
GH
,
Carrier
M
,
Ay
C
, et al
.
American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer
.
Blood Advances
.
2021
;
5
(
4
):
927
-
974
.
52.
Barbui
T
,
Carobbio
A
,
De Stefano
V
.
Thrombosis in myeloproliferative neoplasms during cytoreductive and antithrombotic drug treatment
.
Research and Practice in Thrombosis and Haemostasis
.
2022
;
6
(
1
):
e12657
.
53.
Ferrari
A
,
Carobbio
A
,
Masciulli
A
, et al
.
Clinical outcomes under hydroxyurea treatment in polycythemia vera: a systematic review and meta-analysis
.
Haematologica
.
2019
;
104
(
12
):
2391
-
2399
.
54.
Stevens
SM
,
Woller
SC
,
Bauer
KA
, et al
.
Guidance for the evaluation and treatment of hereditary and acquired thrombophilia
.
J Thromb Thrombolysis
.
2016
;
41
:
154
-
164
.
55.
Stevens
SM
,
Woller
SC
,
Kreuziger
LB
, et al
.
Antithrombotic therapy for VTE disease: second update of the CHEST guideline and expert panel report
.
Chest
.
2021
;
160
(
6
):
e545
-
e608
.
56.
Decousus
H
,
Prandoni
P
,
Mismetti
P
, et al
.
Fondaparinux for the treatment of superficial-vein thrombosis in the legs
.
N Engl J Med
.
2010
;
363
(
13
):
1222
-
1232
.
57.
Kakkos
SK
,
Gohel
M
,
Baekgaard
N
, et al
.
Editor’s choice - European Society for Vascular Surgery (ESVS) 2021 clinical practice guidelines on the management of venous thrombosis
.
Eur J Vasc Endovasc Surg
.
2021
;
61
(
1
):
9
-
82
.
58.
Barco
S
,
Pomero
F
,
Di Minno
MND
, et al
.
Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow-up study
.
J Thromb Haemostasis
.
2017
;
15
(
11
):
2176
-
2183
.
59.
Galanaud
J-P
,
Blaise
S
,
Sevestre
M-A
, et al
.
Long-term outcomes of isolated superficial vein thrombosis in patients with active cancer
.
Thromb Res
.
2018
;
171
:
179
-
186
.
60.
De Stefano
V
,
Ruggeri
M
,
Cervantes
F
, et al
.
High rate of recurrent venous thromboembolism in patients with myeloproliferative neoplasms and effect of prophylaxis with vitamin K antagonists
.
Leukemia
.
2016
;
30
(
10
):
2032
-
2038
.
61.
Farge
D
,
Frere
C
,
Connors
JM
, et al
.
2022 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer, including patients with COVID-19
.
Lancet Oncol
.
2022
;
23
(
7
):
e334
-
e347
.
62.
Ianotto
J-C
,
Couturier
M-A
,
Galinat
H
, et al
.
Administration of direct oral anticoagulants in patients with myeloproliferative neoplasms
.
Int J Hematol
.
2017
;
106
(
4
):
517
-
521
.
63.
Fedorov
K
,
Goel
S
,
Kushnir
M
,
Billett
HH
.
Thrombosis in myeloproliferative neoplasms: treatment outcomes of direct oral anticoagulants and vitamin K antagonists
.
Research and Practice in Thrombosis and Haemostasis
.
2021
;
5
(
6
):
e12574
.
64.
Serrao
A
,
Breccia
M
,
Napolitano
M
, et al
.
A multicenter real-life study on anticoagulant treatment with direct oral anticoagulants in patients with Ph-negative myeloproliferative neoplasms
.
Am J Hematol
.
2020
;
95
(
12
):
E329
-
E332
.
65.
Huenerbein
K
,
Sadjadian
P
,
Becker
T
, et al
.
Direct oral anticoagulants (DOAC) for prevention of recurrent arterial or venous thromboembolic events (ATE/VTE) in myeloproliferative neoplasms
.
Ann Hematol
.
2021
;
100
(
8
):
2015
-
2022
.
66.
Barbui
T
,
De Stefano
V
,
Carobbio
A
, et al
.
Direct oral anticoagulants for myeloproliferative neoplasms: results from an international study on 442 patients
.
Leukemia
.
2021
;
35
(
10
):
2989
-
2993
.
67.
Larsen
T
,
Garresori
H
,
Brekke
J
, et al
.
Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients – 30 months follow-up
.
J Thromb Haemostasis
.
2022
;
20
(
5
):
1166
-
1181
.
68.
De Stefano
V
,
Ghirardi
A
,
Masciulli
A
, et al
.
Arterial thrombosis in Philadelphia-negative myeloproliferative neoplasms predicts second cancer: a case-control study
.
Blood
.
2020
;
135
(
5
):
381
-
386
.
69.
Sekhar
M
,
McVinnie
K
,
Burroughs
AK
.
Splanchnic vein thrombosis in myeloproliferative neoplasms
.
Br J Haematol
.
2013
;
162
(
6
):
730
-
747
.
70.
Stefano
VD
,
Qi
X
,
Betti
S
,
Rossi
E
.
Splanchnic vein thrombosis and myeloproliferative neoplasms: molecular-driven diagnosis and long-term treatment
.
Thromb Haemost
.
2016
;
115
(
02
):
240
-
249
.
71.
How
J
,
Trinkaus
KM
,
Oh
ST
.
Distinct clinical, laboratory and molecular features of myeloproliferative neoplasm patients with splanchnic vein thrombosis
.
Br J Haematol
.
2018
;
183
(
2
):
310
-
313
.
72.
De Stefano
V
,
Vannucchi
AM
,
Ruggeri
M
, et al
.
Splanchnic vein thrombosis in myeloproliferative neoplasms: risk factors for recurrences in a cohort of 181 patients
.
Blood Cancer J
.
2016
;
6
(
11
):
e493
.
73.
Plessier
A
,
Goria
O
,
Cervoni
JP
, et al
.
Rivaroxaban prophylaxis in noncirrhotic portal vein thrombosis
.
NEJM Evidence
.
2022
;
1
(
12
).
74.
Curto-Garcia
N
,
Doyle
AJ
,
Breen
KA
, et al
.
Outcomes of patients receiving direct oral anticoagulants for myeloproliferative neoplasm-associated venous thromboembolism in a large tertiary centre in the UK
.
Br J Haematol
.
2020
;
189
(
3
):
e79
-
e81
.
75.
Tremblay
D
,
Vogel
AS
,
Moshier
E
, et al
.
Outcomes of splanchnic vein thrombosis in patients with myeloproliferative neoplasms in a single center experience
.
Eur J Haematol
.
2020
;
104
(
1
):
72
-
73
.
76.
Hoekstra
J
,
Bresser
EL
,
Smalberg
JH
, et al
.
Long-term follow-up of patients with portal vein thrombosis and myeloproliferative neoplasms
.
J Thromb Haemostasis
.
2011
;
9
(
11
):
2208
-
2214
.
77.
Sant’Antonio
E
,
Guglielmelli
P
,
Pieri
L
, et al
.
Splanchnic vein thromboses associated with myeloproliferative neoplasms: An international, retrospective study on 518 cases
.
Am J Hematol
.
2020
;
95
(
2
):
156
-
166
.
78.
Lavu
S
,
Szuber
N
,
Mudireddy
M
, et al
.
Splanchnic vein thrombosis in patients with myeloproliferative neoplasms: The Mayo clinic experience with 84 consecutive cases
.
Am J Hematol
.
2018
;
93
(
3
):
E61
-
E64
.
79.
Finazzi
G
,
De Stefano
V
,
Barbui
T
.
Splanchnic vein thrombosis in myeloproliferative neoplasms: treatment algorithm 2018
.
Blood Cancer J
.
2018
;
8
(
7
).
80.
Galtier
J
,
Drevon
L
,
Bris
YL
, et al
.
Role of red cell mass evaluation in myeloproliferative neoplasms with splanchnic vein thrombosis and normal hemoglobin value: a study of the France Intergroupe des Syndromes myeloprolifératifs
.
Haematologica
.
2024
.
81.
Maaziz
N
,
Georges
M
,
Basille
D
, et al
.
The co-rebreathing method is a reliable test in determining the red cell mass: the old pots make the best soups [abstract]
.
Hemasphere
.
2023
;
7
(
Suppl
):
e993538d
.
You do not currently have access to this content.
Sign in via your Institution