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Thrombosis Research
j o u r n a l h o m e p a g e : w w w. e l s e v i e r . c o m / l o c a t e / t h r o m r e s

Thrombosis in hematological malignancies: mechanisms and implications

Netanel A. Horowitza,b,*, Benjamin Brennera,b
a
Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, Haifa, Israel
b
Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel

ARTICLE INFO ABSTRACT

Keywords: Thrombotic events are a major cause of morbidity and mortality in cancer. While the association of venous
Hematological malignancies thromboembolic events with cancer is well documented, in recent years arterial events (i.e. acute myocardial
Venous thromboembolism infarction and ischemic strokes) have also emerged as relatively common complications among cancer patients.
Arterial thrombotic events
In hematological malignancies incorporating a heterogeneous group of diseases, the prediction of thrombosis
Risk assessment
Thrombocytopenia
occurrence and/or recurrence is challenging, due to unique disease characteristics. Furthermore, the treatment
of thrombosis in these patients is often complicated because of disease- or therapy-related thrombocytopenia. In
addition, patients with hematological cancers are poorly represented in randomized control clinical trials; hence,
evidence-based guidelines are limited. This review will discuss the incidence of venous and arterial thrombotic
events in common myeloid and lymphoproliferative diseases. Several new mechanisms contributing to cancer-
associated thrombosis will be elaborated. The complicated issue of risk assessment and management of venous
thrombosis in patients with hematological malignancies will be delineated.

Highlights controlled clinical trials, at least in some hematological malignancies,

• Arterial and venous thrombotic events are common in
hematological malignancies.
• Clonal hematopoiesis of indeterminate potential can promote
arterial thrombosis.
• Risk assessment tools for thrombosis and bleeding in these
patients are limited.
• Prospective trials are needed to define anticoagulation strategies
in this setting.
1. Introduction
Thrombosis is a leading cause of morbidity and mortality in cancer
patients. During recent years, efforts have been made to identify among
patients with cancer those who are at high risk of developing venous
and arterial thrombotic events. Clinical trials have been conducted to
evaluate the efficacy and safety of thrombo-prophylaxis and treatment
in this high-risk population. However, data regarding the epidemiology
of thrombotic events in patients with hematological malignancies and,
particularly, their clinical management are limited, as such patients are
under-represented in clinical trials. In addition, disease- or treatment-
related thrombocytopenia increases the risk of bleeding associated
with anticoagulation, which renders the performance of large-scale
challenging. Recently, a large Danish population-based cohort study
assessed the risks of myocardial infarction, ischemic stroke (IS),
venous thromboembolism (VTE), and bleeding (requiring hospital
contact) in patients with hematological cancers [1]. Among 32,141
evaluated patients (2000–2013), the 10‐year absolute risk of any
thromboembolic or bleeding events following hematological cancers
was 19%, with the percentage for myocardial infarction, IS, VTE and
bleeding amounting to 3.3%, 3.5%, 5.2%, and 8.5%, respectively. Of
note, the risk of thromboembolic events overcame that of bleeding in
all the patients, except for those with acute myeloid leukemia (AML),
acute lymphoid leukemia (ALL), or myelodysplastic syndrome (MDS).
Overall, patients with hematological cancer were at increased risk
for acute myocardial infarction (AMI) (hazard ratio (HR) 1.36, 95%
confidence interval (CI) 1.25–1.49), IS (HR 1.22, 95% CI 1.12–1.33),
VTE (HR 3.37, 95% CI 3.13–3.64), and bleeding (HR 2.39, 95% CI
2.26–2.53), relative to the general population [1]. The findings of this
large, well-conducted epidemiological study emphasize the magnitude
of the problem and highlight the need for trials targeting these clinical
settings. The present review will address the issue of thrombotic risk
(arterial and venous) in hematological malignancies, focusing on the
diseases with limited available data. In addition, pathophysiological
mechanisms contributing to VTE occurrence, approaches to VTE
management, and most challenging clinical scenarios will be discussed.

* Corresponding author at: Department of Hematology and Bone Marrow Transplantation, Rambam Health Care Campus, 8, Ha’Aliya Street, Haifa 3109601,
Israel.
E-mail address: n_horowitz@rambam.health.gov.il (N.A. Horowitz).

Received 2 October 2019; Received in revised form 12 January 2020; Accepted 13 January 2020
This article was published as part of a supplement sponsored by the International Conference on Thrombosis and Hemostasis Issues in Cancer.
0049-3848/ © 2020 Published by Elsevier Ltd.
N.A. Horowitz and B. Brenner
2. Acute leukemia
In a population-based cohort study from California (1993–1999),
including 5,934 AML patients, the 2-year cumulative VTE incidence was
5.2%. Sixty-four percent of events occurred within 3 months of AML
diagnosis. Of note, the VTE diagnosis was not associated with reduced
survival at 1 year. The same study also included 2,482 ALL patients.
The 2-year VTE incidence was 4.5% and VTE was associated with a
40% increase in the risk of death at 1 year. Overall, the incidence of
VTE among patients with acute leukemia was similar to that observed
in patients with solid tumors [2]. In the Danish study, the 10-year
incidence of VTE was 12.4 % among AML patients, with an HR of 4.49
(6.14–6.42), while among ALL patients the incidence was 11.24%,
with an HR of 7.42 (3.07–17.97) [1]. In a prospective evaluation of
the incidence, risk factors and outcomes of thromboembolism (TE)
in 1038 children with ALL, TE occurred in 6.1% of children, with
the highest incidence (20.5%) observed those aged 15–17 years. The
TE-associated case fatality rate of 6.4% indicates that TE is a severe
complication of ALL treatment [3].
3. Lymphoma
The rate of arterial and venous thrombotic events in lymphoma
patients was estimated in a meta-analysis that included 29 cohort
studies and 18,018 patients. Among 1,149 recorded events 83.5%
were venous; the majority of them occurred prior to or within the first
3 months of chemotherapy. The global incidence ratio of thrombosis
was 6.4%, while patients with non-Hodgkin lymphoma (NHL) had
a significantly higher ratio than Hodgkin lymphoma (HL) patients
(6.5% versus 4.7%, respectively). Among NHL patients, individuals
with aggressive disease (i.e., diffuse large B cell lymphoma and Burkitt
lymphoma) had a greater risk of VTE events than those with indolent
disease (8.3% versus 6.3%, respectively). A higher risk for VTE in
aggressive NHL was also demonstrated in other studies [4,5]. In the
Danish population-based cohort study the incidence rate and 10-year
HR for VTE were 5.93 and 4.19 in the HL cohort and 11.84 and 3.79
in the NHL cohort. It is of interest that no association with myocardial
infarction or IS was found in in patients with aggressive or indolent
NHL as well as in patients with HL [1].
4. Chronic lymphocytic leukemia
A recent retrospective analysis demonstrated the VTE incidence of
11% in a group of 346 patients with chronic lymphocytic leukemia
(CLL), at a median follow-up of 6 years [6]. In the Danish study, the
10-year incidence rate for thromboembolic complications in CLL
was 7.94% (relative to 6.07 in the comparison cohort) with an HR
of 2.18 (1.80–2.63), whereas the corresponding values for AMI and
IS were 7.68 and 6.20% (HR 1.31 (1.09–1.57) and 0.95 (0.78–1.15),
respectively) [1]. These data imply that it is the rate of VTE and not of
arterial events (at least IS) that is increased among CLL patients, which
could be attributed to the older age of these patients. Of importance,
performance status, poor CLL prognostics factors, concurrent
malignancies, and inherited thrombophilia have all been found to be
associated with VTE occurrence [6].
5. Multiple myeloma
In the aforementioned Danish study, the incidence rate for VTE in
multiple myeloma (MM) was 18% and a 10-year HR of 5.53 (4.51–
6.77) relative to 4.30 (3.92–4.71) in a comparison cohort of matched
individuals from the general population. It is of interest that the
incidence rates for AMI and IS were also high amounting to 9.77% and
7.4, respectively with a HR of 1.87 (1.50–2.33) and 1.3 (1.02–1.65)
relative to the comparison group (6.07 and 6.83, respectively). Higher
rates of arterial TE were also demonstrated by other study groups [7].
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In the analysis of the US Veterans Affairs Hospital database, the crude
incidence of deep vein thrombosis in more than 6,000 MM patients
was about 6% at an 8-year follow-up, which was higher than among
patients without MM [8].
The use of immunomodulatory drugs was shown to increase plasma
levels of factor VIII, von Willebrand factor and protein C resistance,
and to reduce thrombomodulin concentration [9]. In a meta-analysis
of MM patients treated with immunomodulatory drugs, those with
newly diagnosed MM receiving thalidomide alone or in combination
with dexamethasone without thrombo-prophylaxis, had a 3-month
VTE risk of around 4% and 12%, respectively. Likewise, patients with
newly diagnosed MM receiving lenalidomide in combination with
dexamethasone had a 3-month risk of VTE of about 3% [10]. Of note,
the proteasome inhibitor bortezomib was not found to increase the
risk of VTE or arterial TE [11,12]. The thrombo-protective effect of
bortezomib was suggested to be mediated by an increased expression
of the transcription factor KLF2 [13].
VTE risk assessment should be performed in all MM patients
treated with thalidomide or lenalidomide [14]. Recently, two new
risk assessment models have been reported [15,16]. The International
Myeloma Working Group (IMWG) recommends aspirin prophylaxis for
patients with no or one VTE risk factor and low molecular weight
heparin (LMWH) or therapeutic-dose warfarin if two or more risk
factors are present. The same approach is proposed for those receiving
high‐dose dexamethasone, doxorubicin or multi‐agent chemotherapy,
irrespective of preceding risk factors [14]. The 2016 National Institute
of Clinical Excellence (NICE) guidelines reiterate this recommendation,
while acknowledging the relative lack of evidence on the subject.
However, the most recent NICE guidance [17] suggests that either
aspirin or prophylactic dose LMWH may be considered equivalent
for myeloma patients receiving chemotherapy in combination with
immunomodulatory drugs and a corticosteroid.
6. Myeloproliferative neoplasms
In this group of hematological disorders, polycythemia vera
and essential thrombocythemia are associated with increased risk
of thrombosis particularly, with arterial events (e.g., stroke, AMI,
peripheral arterial occlusive disease) accounting for 60–70% of all
thrombotic events [18–21]. Of interest, splanchnic vein thrombosis
is a unique subtype of VTE commonly found in myeloproliferative
neoplasms (MPNs). In a large study of 1,062 patients with Budd-
Chiari syndrome and 855 patients with portal vein thrombosis, the
prevalence of MPNs was 40.9% and 31.5%, respectively [22]. Along
with age and previous thrombotic events, the high cellular counts and,
moreover, the procoagulant phenotypes of blood cells attributed to
genetic alterations in these malignancies have been reported as the
major determinants of thrombosis occurrence [23]. Guidelines for
prophylaxis and treatment of arterial and thrombotic events have been
published and extensively reviewed, but are beyond the scope of this
review.
7. Mechanisms
The three components of the Virchow’s Triad are most pertinent
to cancer patients. The endothelial wall is shifting toward the pro-
coagulant phenotype and tumor cells invade the blood vessel wall.
Stasis of blood is increased due to frequent immobilization and surgery
and blood vessels are often compressed by tumor masses. The third
component of this triad is of exceptional relevance to hematological
malignancies. Thus, leukocytosis, thrombocytosis and elevated hemato-
crit are major contributors to the thrombotic risk in MPNs.
The complexity of the underlying mechanisms has been reflected
in a broad variety of suggested pathways. Tissue factor (TF) is known
to have a crucial role in promoting coagulation and angiogenesis
in cancer [24]. In hematological malignancies, AML, MM and
N.A. Horowitz and B. Brenner
other tumor cells have been found to bear TF and low tissue factor
pathway inhibitor (TFPI) on their membranes and as a result have a
procoagulant phenotype [25]. In recent years, the role of extracellular
vesicles (EVs) in cancer-associated thrombosis (CAT) has emerged.
EVs are lipid bilayer-delimited particles that are naturally released
from a variety of cells, including tumor cells. They carry a cargo of
proteins, nucleic acids, lipids, metabolites, and even organelles from
the parent cell. In the cancer setting, tumor-derived EVs have been
shown to circulate in vivo and express procoagulant molecules (i.e., TF
and phospholipids). EVs induce platelet aggregation through PSGL-1
[26] and exert a procoagulant phenotype on endothelial cells exposed
to EVs derived from AML patients [27]. Furthermore, in EVs obtained
from MM cells, the TF expression is enhanced relative to TFPI and
thrombomodulin expression [28].
Heparanase is an endo-β-D-glucuronidase which cleaves heparan
sulfate chains on cell surfaces and in the extracellular matrix. Hepara-
nase has been demonstrated to enhance angiogenesis, inflammation
and cancer progression [29]. Under physiological conditions, hepara-
nase levels are highest in the placenta, platelets, neutrophils and
monocytes. Thrombin is a selective inducer of heparanase release
from platelets and granulocytes via protease-activated receptor-1
[30]. In MPNs, heparanase staining has appeared to be prominent in
the bone marrow of ET JAK2-positive patients relative to CML and
JAK2-negative patients. Furthermore, JAK2 is involved in heparanase
upregulation via the erythropoietin receptor and heparanase levels
and procoagulant activity is reported to be increased by erythropoietin
and decreased by JAK2 inhibitors [31].
In recent years, the term ‘clonal hematopoiesis of indeterminate
potential’ (CHIP) has been introduced to describe individuals who
acquire somatic mutations in hematopoietic stem cells in the bone
marrow [32–34]. Only in the minority of patients (0.5–1% per year),
these cells can lead to the generation of clones of mutated leukocytes
that populate peripheral blood and ultimately develop acute leukemia.
However, CHIP increases the rate of cardiovascular events (AMI and
IS) by 40% [35]. The genes associated with CHIP are DNMT3A, TET2,
ASXL1, PPM1D, JAK2, TP53, SF3B1 and SRSF2, genes that are often
implicated in the pathogenesis of myelodysplastic syndrome and
AML. Findings from mouse experiments suggest a direct mechanism
by which a CHIP mutation can accelerate atherosclerosis [35]. For
instance, mice bearing mutations in Tet2 in the presence of low-density
lipoprotein receptor deficiency (i.e., atherosclerosis susceptibility)
have demonstrated accelerated lesion formation. Furthermore, cells
with loss-of-function mutations in TET2 show enhanced expression
of pro-inflammatory mediators involved in atherosclerosis, including
interleukin (IL)-1b and IL-6, when stimulated with a classic cardio-
vascular risk factor [36]. All these data give rise to intriguing questions
that will have to be addressed in the future. Should screening for CHIP
be performed and, if so, in whom? How could the cardiovascular
risk in patients with CHIP be estimated? Moreover, what approaches
to the management of the excessive cardiovascular risk could be
recommended in the absence of clinical trials?
8. Risk assessment
In general, patients with cancer should be evaluated for the risk
of VTE occurrence, or recurrence in case of existing CAT [37]. It is
also imperative that if pharmacological anticoagulation or thrombo-
prophylaxis is indicated, the risk of bleeding be assessed. While
several predictive models for CAT development have been proposed
[38–41], the models estimating the bleeding risk associated with
anticoagulation in cancer patients are scarce. The HAS-BLED score is
designed to determine the risk of major bleeding in atrial fibrillation
patients on anticoagulation [42]. Lately, the HAS‐BLED score has
been evaluated in a large cohort of 132,280 VTE patients during the
first 6 months of anticoagulation [43]. In the cancer cohort (20% of
patients) the increase from 3 to 4 points was significant for all bleeds,
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including major ones. When included as an individual covariate along
with components of the HAS‐BLED score, cancer has emerged as the
strongest predictor of major and overall bleeding.
The Khorana score (KRS) has been developed to identify ambulatory
cancer patients receiving chemotherapy who have a high risk for
VTE [38]. However, its validity for patients with hematological
malignancies requires further confirmation. In an attempt to validate
the KRS applicability in lymphoma, Rupa-Matysek and colleagues
assessed 428 HL and diffuse large B-cell lymphoma (DLBCL) patients.
The score failed to discriminate between high- and intermediate-risk
patients with respect to VTE occurrence [44]. In a recent analysis
of 12 clinical trials conducted by the Italian Lymphoma Foundation
(FIL), 40% of patients were characterized as being at ‘high risk’ for
VTE events. However, the actual rate of VTE was only 2.9% in these
patients. Of interest, in this study, DLBCL was found to be associated
with a higher risk for VTE [45]. Overall, these findings suggest that
the KRS might not provide an accurate estimation of the VTE risk in
all lymphoma subtypes and could thus be recommended to be used
for patients with more aggressive lymphoma histology only. Another
predictive model, specific for lymphoma patients (the ThroLy score),
was proposed by Antic et al. [46]. The study population included 1,820
lymphoma patients (a derivation cohort, n=1,236, and a validation
cohort, n=584). The variables independently associated with risk for
VTE were: previous venous/arterial events, mediastinal involvement,
body mass index >30 kg/m2, reduced mobility, extranodal localization,
neutropenia and a hemoglobin level <100 g/L. A high-risk score (i.e.,
>3) had a positive predictive value of 65.2%. The authors conclude
that the ThroLy score is more specific for lymphoma patients than
any other available score targeting thrombosis in cancer patients.
While it looks promising, the ThroLy score needs to be validated in
other lymphoma cohorts prior to its wide implementation as a tool
for precise identification of high-risk patients who should be offered
thrombo-prophylaxis.
9. Management
Several clinical trials have established the role of LMWH in the
treatment of CAT. However, the majority of these trials were conducted
in patients with solid tumors. In the CLOT trial, dalteparin therapy
was associated with a significant (52%) reduction in the risk for VTE
recurrence relative to treatment with vitamin K antagonists (VKA)
[47] Moreover, no significant difference in the rate of major bleeding
between the two arms was observed. Similar results were demonstrated
in the CATCH study, where tinzaparin treatment resulted in a 35% risk
reduction in VTE recurrence compared to VKA therapy. Once again,
the rate of major bleeding was equal in both arms [48].
The International Clinical Practice Guidelines recommend LMWH
for the initial treatment of established VTE in patients with cancer.
Then, a once-daily regimen of LMWH is generally recommended [49]
After 3–6 months, termination or continuation of anticoagulation
should be based on individual assessment. The use of direct oral
anticoagulants (DOACs) in the CAT setting continues to be tested in
clinical trials. The Hokusai trial demonstrated the non-inferiority of
edoxaban to dalteparin for the composite end point of VTE recurrence
and major bleeding [50]. Similar findings were reported in the
SELECT-D trial comparing rivaroxaban and dalteparin in a similar study
design [51]. Of note, an increase in gastrointestinal (and potentially
genitourinary) bleeding events was observed in the DOAC arms. The
ADAM VTE trial compared the use of apixaban and dalteparin in active
cancer-associated VTE [52]. Oral apixaban was associated with low
VTE recurrence rates (0.7% versus 6.3%, p=0.028), while there was
no significant difference in the risk of major bleeding. In all the trials,
the number of patients with hematological cancers was low (10.5%,
2.5% and 10%, respectively).
When considering the use of DOACS for the treatment of CAT, their
potential interactions with anti-cancer medications should be taken
N.A. Horowitz and B. Brenner
into account. For example, imatinib, crizotinib and other tyrosine
kinase inhibitors are known to inhibit CYP 3A4, and may therefore
reduce the effect of DOACS in the plasma. Vinblastine and doxorubicin
are known inducers of P-glycoprotein, and hence may also reduce
DOAC plasma levels and activity [53,54]. Data from other clinical
trials (e.g., Caravaggio) are expected to solidify the evidence on the
efficacy and safety of these agents.
Recently, Soff et al. reported the experience of rivaroxaban treatment
in 1,072 CAT patients at the Memorial Sloan Kettering Cancer Center
[55]. Again, just 8% of patients had hematologic malignancies. Six-
month cumulative incidence of recurrent VTE and major bleeding
were 4.2% and 2.2%, respectively, with 73% of major bleeds occurring
in the gastrointestinal tract. Of note, the elderly (aged over 75 years)
had similar rates of recurrent thrombosis and bleeding as those aged
under 75 years. Since patients with hematological malignancies are
under-represented in these studies, real-life information from large
datasets is crucial for developing guidance on VTE management in
this most challenging clinical setting.
Thrombocytopenia is common in hematological patients as a result
of bone marrow infiltration by tumor cells, toxicity of chemotherapy
or other targeted therapies, immune mediated, stem cell conditioning
regimens or radiation. In a recent observational cohort study of
patients experiencing VTE during periods of treatment-related
thrombocytopenia, 67 patients received anticoagulation and 88% of
them were managed with platelet transfusion support for a goal of
50×109/L. Still, 31 patients experienced bleeding events. The majority
of events were non-major/non-clinically relevant [56]. Similar
findings were reported in the study by Houghton et al. [57]. In this
study, withholding anticoagulation was associated with a substantial
‘trade off’ of recurrent VTE.
Recently, guidance from the SSC of the ISTH regarding the manage-
ment of CAT patients with thrombocytopenia have been published
[58]. In thrombocytopenic (i.e., <50,000/μL) patients at high risk
for thrombosis progression or recurrence (symptomatic segmental or
more proximal pulmonary embolism, proximal deep vein thrombosis,
or a history of or recurrent/progressive thrombosis) full-dose anti-
coagulation in conjunction with platelet transfusion should be
administered. For patients at lower risk, a dose‐modification strategy
using 50% or prophylactic‐dose LMWH may be considered. In severe
thrombocytopenia (i.e., <25,000/μL) anticoagulation should be
withheld, although prophylactic doses might be reasonable in patients
with a platelet count >10,000/μL. Inferior vena cava filter placement
should be considered only in patients with absolute contraindications
to anticoagulation. LMWH is currently the preferred anticoagulant
among patients with CAT and thrombocytopenia, and DOACs are
not recommended. Prospective studies are warranted to identify the
optimal anticoagulation dose and transfusion strategy in this setting.
10. Conclusions
Large datasets and registries provide real-world evidence regarding
the epidemiology of thrombosis in hematological malignancies.
Mechanisms of thrombosis in hematological malignancies are
closely related to tumor biology. Personalized risk assessment of
thrombosis and bleeding is mandatory in patients with hematological
malignancies. Risk-assessment tools based on disease-, patient- and
therapy-associated risk factors need to be developed. Clinical trials
targeting thrombocytopenic patients with hematological malignancies
should be designed. These studies should also explore the role of low-
intensity anticoagulation and DOACs in these complicated clinical
scenarios.
Funding
None.
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Conflict of interest statement:
The authors declare no conflicts of interest.
References
[1] K. Adelborg, P. Corraini, B. Darvalics, et al., Risk of thromboembolic and bleeding
outcomes following hematological cancers: a Danish population-based cohort study,
J. Thromb. Haemost. 17 (2019) 1305–1318.
[2] G.H. Ku, R.H. White, H.K. Chew, et al., Venous thromboembolism in patients with
acute leukemia: incidence, risk factors, and effect on survival, Blood 113 (2009)
3911–3917.
[3] R. Tuckuviene, S. Ranta, B.K. Albertsen, et al., Prospective study of thromboem-
bolism in 1038 children with acute lymphoblastic leukemia: a Nordic Society of
Pediatric Hematology and Oncology (NOPHO) study, J. Thromb. Haemost. 14
(2016) 485–494.
[4] I.H. Borg, M.D. Bendtsen, M. Bogsted, et al., Incidence of venous thromboembo-
lism in patients with diffuse large B-cell lymphoma, Leuk. Lymphoma 57 (2016)
2771–2776.
[5] I.L. Gade, S. Braekkan, I.A. Naess, et al., Epidemiology of venous thromboembolism
in hematological cancers: the Scandinavian Thrombosis and Cancer (STAC) cohort,
Thromb. Res. 158 (2017) 157–160.
[6] M. Simkovic, P. Vodarek, M. Motyckova, et al., Venous thromboembolism in
patients with chronic lymphocytic leukemia, Thromb. Res. 136 (2015) 1082–1086.
[7] A.K. Stewart, S.V. Rajkumar, M.A. Dimopoulos, et al., Carfilzomib, lenalidomide,
and dexamethasone for relapsed multiple myeloma, N. Engl. J. Med. 372 (2015)
142–152.
[8] S.Y. Kristinsson, T.R. Fears, G. Gridley, et al., Deep vein thrombosis after monoclo-
nal gammopathy of undetermined significance and multiple myeloma, Blood 112
(2008) 3582–3586.
[9] F.W. Leebeek, Update of thrombosis in multiple myeloma, Thromb. Res. 140 Suppl
1 (2016) S76–S80.
[10] M. Carrier, G. Le Gal, J. Tay, et al., Rates of venous thromboembolism in multi-
ple myeloma patients undergoing immunomodulatory therapy with thalidomide or
lenalidomide: a systematic review and meta-analysis, J. Thromb. Haemost. 9 (2011)
653–663.
[11] P. Richardson, R. Schlag, N. Khuageva, et al., Characterization of haematological
parameters with bortezomib-melphalan-prednisone versus melphalan-prednisone
in newly diagnosed myeloma, with evaluation of long-term outcomes and risk of
thromboembolic events with use of erythropoiesis-stimulating agents: analysis of
the VISTA trial, Br. J. Haematol. 153 (2011) 212–221.
[12] W. Li, R.F. Cornell, D. Lenihan, et al., Cardiovascular complications of novel multi-
ple myeloma treatments, Circulation 133 (2016) 908–912.
[13] L. Nayak, H. Shi, G.B. Atkins, et al., The thromboprotective effect of bortezomib
is dependent on the transcription factor Kruppel-like factor 2 (KLF2), Blood 123
(2014) 3828–3831.
[14] A. Palumbo, S.V. Rajkumar, M.A. Dimopoulos, et al., Prevention of thalidomide-
and lenalidomide-associated thrombosis in myeloma, Leukemia 22 (2008) 414–423.
[15] A. Li, Q. Wu, S. Luo, et al., Derivation and validation of a risk assessment model
for immunomodulatory drug-associated thrombosis among patients with multiple
myeloma, J. Natl. Compr. Cancer Netw. 17 (2019) 840–847.
[16] K.M. Sanfilippo, S. Luo, T.F. Wang, et al., Predicting venous thromboembolism in
multiple myeloma: development and validation of the IMPEDE VTE score, Am. J.
Hematol. 94 (2019) 1176–1184.
[17] Venous thromboembolism in over 16s: reducing the risk of hospital-acquired deep
vein thrombosis or pulmonary embolism, Available at https://www.nice.org.uk/
guidance/ng89/chapter/Recommendations#interventions-for-people-with-cancer,
Accessed in September 2019.
[18] A. Tefferi, M. Elliott, Thrombosis in myeloproliferative disorders: prevalence, prog-
nostic factors, and the role of leukocytes and JAK2V617F, Semin. Thromb. Hemost.
33 (2007) 313–320.
[19] A. Falanga, M. Marchetti, Thrombosis in myeloproliferative neoplasms, Semin.
Thromb. Hemost. 40 (2014) 348–358.
[20] A. Falanga, M. Marchetti, Thrombotic disease in the myeloproliferative neoplasms,
Hematology Am. Soc. Hematol. Educ. Program 2012 (2012) 571–581.
[21] M. Sekhar, Prevention and management of thrombosis in myeloproliferative neo-
plasms, Clin. Adv. Hematol. Oncol. 15 (2017) 178–181.
[22] M.A. Elliott, A. Tefferi, Thrombosis and haemorrhage in polycythaemia vera and
essential thrombocythaemia, Br. J. Haematol. 128 (2005) 275–290.
[23] T. Barbui, G. Finazzi, A. Falanga, Myeloproliferative neoplasms and thrombosis,
Blood 122 (2013) 2176–2184.
[24] F.R. Rickles, A. Falanga, Molecular basis for the relationship between thrombosis
and cancer, Thromb. Res. 102 (2001) V215–V224.
[25] Y. Nadir, T. Katz, G. Sarig, et al., Hemostatic balance on the surface of leuke-
mic cells: the role of tissue factor and urokinase plasminogen activator receptor,
Haematologica 90 (2005) 1549–1556.
[26] N.S. Key, P. Chantrathammachart, P.W. Moody, J.Y. Chang, Membrane microparti-
cles in VTE and cancer, Thromb. Res. 125 Suppl 2 (2010) S80–S83.
[27] I. Tzoran, A. Rebibo-Sabbah, B. Brenner, A. Aharon, Disease dynamics in patients
with acute myeloid leukemia: new biomarkers, Exp. Hematol. 43 (2015) 936–943.
N.A. Horowitz and B. Brenner
[28] M. Zarfati, I. Avivi, B. Brenner, et al., Extracellular vesicles of multiple myeloma
cells utilize the proteasome inhibitor mechanism to moderate endothelial angiogen-
esis, Angiogenesis 22 (2019) 185–196.
[29] Y. Nadir, B. Brenner, L. Fux, et al., Heparanase enhances the generation of activated
factor X in the presence of tissue factor and activated factor VII, Haematologica 95
(2010) 1927–1934.
[30] M. Tatour, M. Shapira, E. Axelman, et al., Thrombin is a selective inducer of hep-
aranase release from platelets and granulocytes via protease-activated receptor-1,
Thromb. Haemost. 117 (2017) 1391–1401.
[31] I. Kogan, D. Chap, R. Hoffman, et al., JAK-2 V617F mutation increases heparanase
procoagulant activity, Thromb. Haemost. 115 (2016) 73–80.
[32] S. Jaiswal, P. Fontanillas, J. Flannick, et al., Age-related clonal hematopoiesis asso-
ciated with adverse outcomes, N. Engl. J. Med. 371 (2014) 2488–2498.
[33] D.P. Steensma, R. Bejar, S. Jaiswal, et al., Clonal hematopoiesis of indeterminate
potential and its distinction from myelodysplastic syndromes, Blood 126 (2015)
9–16.
[34] L. Busque, M. Buscarlet, L. Mollica, R.L. Levine, Concise review: age-related clonal
hematopoiesis: stem cells tempting the devil, Stem Cells 36 (2018) 1287–1294.
[35] S. Jaiswal, P. Natarajan, A.J. Silver, et al., Clonal hematopoiesis and risk of athero-
sclerotic cardiovascular disease, N. Engl. J. Med. 377 (2017) 111–121.
[36] J.J. Fuster, S. MacLauchlan, M.A. Zuriaga, et al., Clonal hematopoiesis associated
with TET2 deficiency accelerates atherosclerosis development in mice, Science 355
(2017) 842–847.
[37] N.S. Key, A.A. Khorana, N.M. Kuderer, et al., Venous thromboembolism prophylaxis
and treatment in patients with cancer: ASCO clinical practice guideline update, J.
Clin. Oncol. (2019) doi:10.1200/JCO.19.01461.
[38] A.A. Khorana, N.M. Kuderer, E. Culakova, et al., Development and validation of
a predictive model for chemotherapy-associated thrombosis, Blood 111 (2008)
4902–4907.
[39] R. Patell, L. Rybicki, K.R. McCrae, A.A. Khorana, Predicting risk of venous throm-
boembolism in hospitalized cancer patients: utility of a risk assessment tool, Am. J.
Hematol. 92 (2017) 501–507.
[40] N.M. Kuderer, M.S. Poniewierski, E. Culakova, et al., Predictors of venous thrombo-
embolism and early mortality in lung cancer: results from a global prospective study
(CANTARISK), Oncologist 23 (2018) 247–255.
[41] G.T. Gerotziafas, A. Taher, H. Abdel-Razeq, et al., A predictive score for throm-
bosis associated with breast, colorectal, lung, or ovarian cancer: the prospective
COMPASS-Cancer-Associated Thrombosis Study, Oncologist 22 (2017) 1222–1231.
[42] R. Pisters, D.A. Lane, R. Nieuwlaat, et al., A novel user-friendly score (HAS-BLED)
to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro
Heart Survey, Chest 138 (2010) 1093–1100.
[43] J.D. Brown, A.J. Goodin, G.Y.H. Lip, V.R. Adams, Risk stratification for bleeding
complications in patients with venous thromboembolism: application of the HAS-
BLED bleeding score during the first 6 months of anticoagulant treatment, J. Am.
Heart. Assoc. 7 (2018) e007901.
S62
Thrombosis Research 191S1 (2020) S58–S62
[44] J. Rupa-Matysek, M. Lembicz, E.K. Rogowska, et al., Evaluation of risk factors and
assessment models for predicting venous thromboembolism in lung cancer patients,
Med. Oncol. 35 (2018) 63.
[45] R.M. Santi, M. Ceccarelli, G. Catania, et al., PO-03 – Khorana score and histotype
predict the incidence of early venous thromboembolism (VTE) in non-hodgkin lym-
phoma (NHL). A pooled data analysis of twelve clinical trials of Fondazione Italiana
Linfomi (FIL), Thromb. Res. 140 Suppl 1 (2016) S177.
[46] D. Antic, N. Milic, S. Nikolovski, et al., Development and validation of multivari-
able predictive model for thromboembolic events in lymphoma patients, Am. J.
Hematol. 91 (2016) 1014–1019.
[47] A.Y. Lee, M.N. Levine, R.I. Baker, et al., Low-molecular-weight heparin versus a
coumarin for the prevention of recurrent venous thromboembolism in patients with
cancer, N. Engl. J. Med. 349 (2003) 146–153.
[48] A.Y.Y. Lee, P.W. Kamphuisen, G. Meyer, et al., Tinzaparin vs warfarin for treatment
of acute venous thromboembolism in patients with active cancer: a randomized
clinical trial, JAMA 314 (2015) 677–686.
[49] D. Farge, C. Frere, J.M. Connors, et al., 2019 International clinical practice guide-
lines for the treatment and prophylaxis of venous thromboembolism in patients with
cancer, Lancet Oncol. 20 (2019) e566–e581.
[50] G.E. Raskob, N. van Es, P. Verhamme, et al., Edoxaban for the treatment of cancer-
associated venous thromboembolism, N. Engl. J. Med. 378 (2018) 615–624.
[51] A.M. Young, A. Marshall, J. Thirlwall, 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. 36
(2018) 2017–2023.
[52] R.D. McBane 2nd, W.E. Wysokinski, J.G. Le-Rademacher, et al., Apixaban and
dalteparin in active malignancy-associated venous thromboembolism: the ADAM
VTE trial, J. Thromb. Haemost. (2019) doi:10.1111/jth.14662.
[53] N.J. Short, J.M. Connors, New oral anticoagulants and the cancer patient, Oncologist
19 (2014) 82–93.
[54] A.Y. Lee, E.A. Peterson, Treatment of cancer-associated thrombosis, Blood 122
(2013) 2310–2317.
[55] G.A. Soff, J. Mones, C. Wilkins, et al., Rivaroxaban treatment of cancer-associated
venous thromboembolism: Memorial Sloan Kettering Cancer Center institutional
experience, Res. Pract. Thromb. Haemost. 3 (2019) 349–356.
[56] B.T. Samuelson Bannow, R.B. Walter, T.B. Gernsheimer, D.A. Garcia, 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. 44 (2017) 442–447.
[57] D.E. Houghton, N.S. Key, N.A. Zakai, et al., Analysis of anticoagulation strategies for
venous thromboembolism during severe thrombocytopenia in patients with hemato-
logic malignancies: a retrospective cohort, Leuk. Lymphoma 58 (2017) 2573–2581.
[58] B.T. Samuelson Bannow, A. Lee, A.A. Khorana, et al., Management of cancer-asso-
ciated thrombosis in patients with thrombocytopenia: guidance from the SSC of the
ISTH, J. Thromb. Haemost. 16 (2018) 1246–1249.