biomolecules

Review
Venous Thromboembolism and Cancer: A Comprehensive
Review from Pathophysiology to Novel Treatment
Mario Enrico Canonico 1 , Ciro Santoro 1, *, Marisa Avvedimento 1 , Giuseppe Giugliano 1 ,
Giulia Elena Mandoli 2 , Maria Prastaro 1 , Anna Franzone 1 , Raffaele Piccolo 1 , Federica Ilardi 1,3 ,
Matteo Cameli 2 and Giovanni Esposito 1

1 Department of Advanced Biomedical Sciences, Federico II University Hospital, 80131 Naples, Italy;
marioenrico.canonico@unina.it (M.E.C.); marisa.avvedimento@unina.it (M.A.);
giuseppe.giugliano@unina.it (G.G.); prastaro@unina.it (M.P.); anna.franzone@unina.it (A.F.);
raffaele.piccolo@unina.it (R.P.); fedeilardi@gmail.com (F.I.); espogiov@unina.it (G.E.)
2 Division of Cardiology, Department of Medical Biotechnologies, University of Siena, 53100 Siena, Italy;
giulia_elena@hotmail.it (G.E.M.); matteo.cameli@yahoo.com (M.C.)
3 Mediterranea Cardiocentro, 80122 Naples, Italy
* Correspondence: ciro.santoro@unina.it; Tel.: +39-817463663

Abstract: Acute thrombotic events can unveil occult cancer, as they are its first manifestation in about
20 to 30% of all cases. Malignancy interacts in an intricate way with the hemostatic system, promoting
both thrombosis and bleeding. The main pathway involved in these reactions involves the activation
of tumor-associated procoagulant factors, which eventually results in clot formation. The clinical
manifestation of cancer-related thrombotic events mainly involves the venous side, and manifests



in a broad spectrum of conditions, including unusual sites of venous thrombosis. The selection of


patients who have a balanced risk–benefit profile for management of anticoagulation is complex,
Citation: Canonico, M.E.; Santoro, C.;
given individual patient goals and preferences, different prognosis of specific cancers, common
Avvedimento, M.; Giugliano, G.;
Mandoli, G.E.; Prastaro, M.;
comorbidities, potential drug–drug interactions, underweight states, and the competing risks of
Franzone, A.; Piccolo, R.; Ilardi, F.; morbidity and mortality. Anticoagulant treatment in cancer settings is broadly debated, considering
Cameli, M.; et al. Venous the potential application of direct oral anticoagulants in both thromboprophylaxis and secondary
Thromboembolism and Cancer: A prevention, having demonstrated its efficacy and safety compared to conventional treatment. This
Comprehensive Review from review aims to provide a brief overview of the pathophysiology and management of cancer-related
Pathophysiology to Novel Treatment. thrombosis, summarizing the results obtained in recent clinical trials.
Biomolecules 2022, 12, 259. https://
doi.org/10.3390/biom12020259 Keywords: venous thromboembolism; cancer; anticoagulation; risk stratification; cardio-oncology
Academic Editor: Christian Schulz

Received: 31 December 2021

Accepted: 3 February 2022
1. Introduction
Published: 4 February 2022
The intricate connection between malignancies and the hemostatic system has been
Publisher’s Note: MDPI stays neutral known for a long time. Cancer cells override the coagulation pathway, to enhance their
with regard to jurisdictional claims in diffusion, by releasing procoagulant factors which eventually activate platelets and inflam-
published maps and institutional affil- matory cells, which in turn stimulate angiogenesis and clot formation. Indeed, thrombotic
iations.
events could, as its first manifestation, unveil an occult malignancy [1]. Of interest, about
20 to 30% of all first venous thrombotic events are cancer related [2,3].
When a thrombotic event occurs, the presence of active malignancy is considered a
determinant of unfavorable evolution, when compared to traditional counterparts. There-
Copyright: © 2022 by the authors.
Licensee MDPI, Basel, Switzerland.
fore, in this setting, anticoagulation management should be prompt and aggressive. The
This article is an open access article
decision on treatment duration should consider the higher recurrence risk present in an
distributed under the terms and oncologic setting [4], as the presence of cancer itself is considered a “non-transient” risk
conditions of the Creative Commons factor for venous thromboembolism (VTE). On the other hand, cancer may increase the
Attribution (CC BY) license (https:// rate of bleeding events that account for higher mortality, with an incidence of 10% in solid
creativecommons.org/licenses/by/ tumors, and an even higher proportion in patients with hematologic malignancies [5].
4.0/). Consequently, treatment of venous thromboembolism (VTE) in patients with cancer can

Biomolecules 2022, 12, 259. https://doi.org/10.3390/biom12020259 https://www.mdpi.com/journal/biomolecules

Biomolecules 2022, 12, 259 2 of 14

be challenging, faced with serious complications including increased risk of bleeding,

potential drug–drug interactions that accompany chemotherapy, underweight states, and
the competing risks of morbidity and mortality.

2. Epidemiology and Risk Stratification

Several registries involved in the analysis of cancer and coagulation crosstalk provided
precious information about the incidence of venous thrombosis in cancer settings [6–10]. In
the Multiple Environmental and Genetic Assessment of risk factor for venous thrombosis
(MEGA) study, more than 3000 patients who experienced DVT between 1999 and 2002
were included, and were matched with healthy controls. Among them, the risk of DVT
was increased sevenfold by the presence of malignancies. Additionally, in patients with
malignancies, the occurrence of DVT appeared to be high during the first year after cancer
diagnosis, reaching its highest incidence within the first three months (adjusted OR, 53.5;
95% CI, 8.6–334.3) and decreasing as time progressed [11]. One possible explanation could
lie in the natural course of the disease; cancer treatments (chemo- and hormonal therapy,
need for blood transfusion, surgery, etc.), and their prothrombic effects, are concentrated
within the first year after diagnosis, whilst subsequent cancer remission or death eventually
reduce the occurrence of DVT.
Of interest, the incidence of cancer-related venous thrombosis showed a hyperbolic
distribution over the last decades, with a 1.5% incidence rate in the late 1980s, and reach-
ing 4.6% in the early 2000s [12]. This increase could be the consequence of different
factors; firstly, improvements in diagnostic testing and the spreading acknowledgment
of a solid link between cancer and venous thrombotic events; secondly, it could be the
effect of multiple novel treatments with both direct and indirect iatrogenic effects, due to
prolonged survival.
The risk of developing venous thrombotic events, in oncologic settings, depends on
several cancer-related and patient-related factors (Table 1).

Table 1. Risk factors for venous thrombosis.

Cancer-Related Patient-Related
Type of cancer
Older age.
- High risk: pancreas, brain, lung, ovarian, lymphoma, Prolonged immobility.
myeloma, kidney, stomach and bone cancer; Prior history of venous thrombosis.
- Low risk: breast, prostate, melanoma, Black ethnicity.
testicular cancer. Prothrombotic mutation.
Stage of cancer Indwelling catheter.
- Advanced stage and initial period after diagnosis. Comorbidities (≥3):
Treatment - Arterial thromboembolism;
- Pulmonary disease;
- Chemo- and hormonal therapy;
- Renal disease;
- Anti-angiogenic therapy;
- Infection;
- Erythropoiesis stimulating agents;
- Anemia.
- Blood transfusions.

The type of malignancy seems to influence the risk of venous thrombosis, such that
high-risk cancers (pancreas, brain, lung, ovarian, lymphoma, myeloma, kidney, stomach,
and bone cancer) and low-risk cancers (breast, prostate, malignant melanoma, and tes-
ticular) can be identified [13]. Cancer features of biological aggressiveness, such as early
metastatic diffusion and consequential dismal prognosis, correlate to incidence rates of
venous thrombosis [14], as evidenced by Tim JF et al., who showed a positive association in
incidence rates of venous thrombotic events plotted against one-year relative mortality for
different types of cancer [15].
In oncologic patients, several conditions not associated with cancer, defined as patient-
related risk factors, might also increase the risk of thrombotic events. Among them, age and
 Biomolecules 2022, 12, 259 3 of 13

in incidence rates of venous thrombotic events plotted against one-year relative mortality
Biomolecules 2022, 12, 259 for different types of cancer [15]. 3 of 14
In oncologic patients, several conditions not associated with cancer, defined as patient-
related risk factors, might also increase the risk of thrombotic events. Among them, age and
history of previous venous thrombosis are the most recognized. Additionally, as demon-
history of previous venous thrombosis are the most recognized. Additionally, as demon-
strated in a retrospective analysis of 68,142 colorectal cancer patients, the concomitant pres-
strated in a retrospective analysis of 68,142 colorectal cancer patients, the concomitant
ence of chronic comorbidities (such as pulmonary and renal disease, infection, and anemia)
presence of chronic comorbidities (such as pulmonary and renal disease, infection, and
increases the risk of venous thrombosis by a factor of two within one year after diagnosis
anemia) increases the risk of venous thrombosis by a factor of two within one year after di-
[16]. Other common risk factors for venous thrombosis in non-cancer populations, which
agnosis
may recur in Other
[16]. common
this context, risk
such as factors for immobility
prolonged venous thrombosis in non-cancer
after a surgical populations,
treatment, place-
which
ment of central venous catheters (CVC), or prothrombotic mutations, should also be treatment,
may recur in this context, such as prolonged immobility after a surgical a con-
placement
cern when of centralthrombotic
assessing venous catheters (CVC),patients.
risk in cancer or prothrombotic
[11,17]. mutations, should also be a
concern when assessing thrombotic risk in cancer patients. [11,17].
3. Biological Mechanisms of Cancer-Related Thrombosis
3. Biological Mechanisms of Cancer-Related Thrombosis
Malignancy interacts in an intricate way with the hemostatic system, enabling both
Malignancy
thrombosis interacts inClinical
and hemorrhage. an intricate way
factors, with the
combined hemostatic
with system,
disease-specific enabling
features andboth
thrombosis
biological procoagulant mechanisms, contribute to the definition of overall thrombotic and
and hemorrhage. Clinical factors, combined with disease-specific features
biological procoagulant
risk in patients mechanisms,
with cancer. contribute
The pathogenesis to the definition
of cancer-induced VTE isof overall thrombotic
multifactorial and
risk in patients
involves severalwith cancer. The
overlapping pathogenesis
pathways, of cancer-induced
including direct coagulationVTE is multifactorial
pathway activation, and
involves several
the induction overlapping pathways,
of inflammatory including
responses, the direct
inhibition coagulation
of fibrinolytic pathway
activity, and activation,
tumor
the inductionplatelet
cell-induced of inflammatory
aggregationresponses,
(Figure 1).the inhibition of fibrinolytic activity, and tumor
cell-induced platelet aggregation (Figure 1).

Figure 1. Crosstalk between malignant cells and the hemostatic system.

Figure 1. Crosstalk between malignant cells and the hemostatic system.
3.1. Direct Coagulation Pathway Activation
3.1. Direct Coagulation Pathway Activation
Tumor cells release a variety of procoagulant substances, such as tissue factor (TF),
Tumor cells
TF-positive release a variety
tumor-derived of procoagulant
microparticles (MPs),substances, such as tissue
cancer procoagulant factor
(CP) (TF), and
factor,
TF-positive tumor-derived microparticles (MPs), cancer procoagulant (CP) factor, and
heparinase, resulting in a hypercoagulable state [18]. The up-regulation of TF, a primary
heparinase, resulting in a hypercoagulable state [18]. The up-regulation of TF, a primary
initiator of the coagulation cascade, has been suggested as the main mechanism through
initiator of the coagulation cascade, has been suggested as the main mechanism through
which cancer induces fibrin formation. It forms a complex with activated factor VII to
which cancer induces fibrin formation. It forms a complex with activated factor VII to
trigger blood coagulation by proteolytic activation of factors IX and X. Procoagulant TF
trigger blood coagulation by proteolytic activation of factors IX and X. Procoagulant TF
can be vacuolized and released in tumor microparticles rich in TF, which disseminate
can be vacuolized and released in tumor microparticles rich in TF, which disseminate into
into the body and cause both systemic and localized thrombotic events. Mice injected
the body and cause both systemic and localized thrombotic events. Mice injected with TF-
with TF-enriched microparticles showed a higher incidence of disseminated intravascular
enriched microparticles showed a higher incidence of disseminated intravascular coagu-
coagulation (DIC)-like syndrome, thus reinforcing this pathophysiological hypothesis [19].
Different cancer histotypes constitutively overexpress TF, higher expression levels of which
seem to be associated with a more aggressive pattern of tumor growth and vascularity.
• Moreover, CP, which is highly expressed by proliferating blast cells and some solid
tumors, can directly activate Factor X, shifting the hemostatic balance towards a
prothrombotic condition [20,21].
• MPs represent an emerging mechanism of cancer-promoted clotting activation. MPs
are fragments shed from the plasma membrane of numerous cell types—including
tumors, blood cells, and endothelial cells—on exposure to stress conditions, and act as
Biomolecules 2022, 12, 259 4 of 14

mediators of cell–cell communication [22]. Furthermore, MPs can also play a role in
cancer progression, due to their ability to positively influence angiogenesis [23].
• Angiogenesis plays a significant role in tumor progression, and, to date, evidence
from several studies supports the use of low molecular weight heparin (LMWH)
as a therapeutic tool in cancer patients, by utilizing the anti-metastatic properties
of LMWH [24]. This effect seems to be linked to different synergistic mechanisms,
among which are the prevention of cancer-induced hypercoagulation, cancer cell
proliferation, apoptosis, and angiogenesis [25]. Specifically, LMWH expresses anti-
angiogenic activity via binding and inhibiting angiogenic growth factors, such as
Vascular Endothelial Growth factor (VEGF), and interferes with fibrin formation,
resulting in inhibition of cancer metastasis [26].

3.2. Induction of Inflammatory Responses

The production of proinflammatory cytokines (interleukin 1b (IL-1b), IL-6, IL-1β, tu-
mor necrosis factor a (TNF-a), and lipopolysaccharides) and proangiogenic factors (mainly
vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF)) by malignant
cells further contributes to pro-coagulant status by inducing cell adhesion and vascular cell
activation [27]. It has been extensively demonstrated that interleukin levels are significantly
elevated in cancer patients compared to healthy controls, especially in those with VTE. The
inflammatory response, through increased release of TF, von Willebrand factor, plasmino-
gen activator inhibitor (PAI-1), and VEGF induced by endothelial cells, together with a
down-regulation of thrombin activity and the protein C system, can lead to a procoagulant
phenotype in patients with cancer.
Tumor cells can also activate leukocytes by direct cell–cell adhesion. Neutrophils
and monocytes/macrophages activate release procoagulant enzymes and expose, on their
surface, high levels of TF and adhesion molecules for platelets and endothelial cells, thus
leading to fibrin formation and deposition. Furthermore, recent evidence suggests that
inflammatory responses to cancer can also result in the formation of neutrophil extracellular
traps (NETs), which are scaffolds made of externalized DNA, histones, and proteases.
NETs have a strong pro-thrombotic effect, providing a stimulus for platelet adhesion and
aggregation; conversely, activated platelets can promote their formation and release.

3.3. Inhibition of Fibrinolytic System

In addition to the induction of fibrin clots, cancer can also result in an anticoagulant
effect by interacting with the fibrinolytic system. Indeed, cancer tissue can express fibri-
nolytic proteins, such as the plasminogen activators (urokinase-type plasminogen activator
(uPA) and tissue-type plasminogen activator (tPA)), their inhibitors (PAI-1 and -2), and
their receptors. PAI-1 is the major inhibitor of plasminogen activation by tPA, and therefore
is an inhibitor of fibrin clot degradation [28]. Elevated levels of PAI-1 antigen and activity
have been found in patients with cancer, which was combined to VTE susceptibility [29].

3.4. Tumor Cell-Induced Platelet Aggregation

There is growing evidence that platelet function plays an important role in promoting
the hypercoagulable state of patients with cancer [30]. Tumor cells activate platelets through
direct cancer cell–platelet adhesion, and/or by tumor secretion of platelet-activating
molecules (i.e., ADP, thrombin, matrix metalloproteinases, IL-6) which lead to platelet
adhesion/aggregation [31]. Among adhesion mechanisms, selectins expressed on platelets,
leukocytes, and endothelium tissue can bind tumor cells to form aggregates. Specifically,
P-selectin, expressed on the surface of activated platelets, binds to many types of human
cancer cells, and this interaction can also promote tumor growth and metastasis [32]. Ac-
tivated platelets can mediate the onset of hypercoagulability in cancer patients by direct
clotting activation and thrombus formation, or by interacting with other blood cells. As
reported, platelets stimulate the release of NETs via leukocytes, and their interaction with
endothelial cells is relevant in platelet-mediated cancer-associated VTE.
 human cancer cells, and this interaction can also promote tumor growth and metastasis
[32]. Activated platelets can mediate the onset of hypercoagulability in cancer patients by
direct clotting activation and thrombus formation, or by interacting with other blood cells.
As reported, platelets stimulate the release of NETs via leukocytes, and their interaction
Biomolecules 2022, 12, 259 with endothelial cells is relevant in platelet-mediated cancer-associated VTE. 5 of 14

4. Clinical Presentation
4. Clinical Presentation
Cancer-related thrombotic events usually occur on the venous side, and manifest
Cancer-related
clinically in a broadthrombotic
spectrum ofevents usuallyalso
conditions, occur on the venous
addressed side, and
as Trousseau’s manifest that
syndrome,
clinically
includes in a broad
venous spectrum
and arterialofthrombosis,
conditions, also addressed thrombotic
non-bacterial as Trousseau’s syndrome, that
endocarditis (NBTE),
includes venous and arterial thrombosis, non-bacterial thrombotic
thrombotic microangiopathy (TMA), and veno-occlusive disease (VOD). endocarditis (NBTE),
thrombotic
Venousmicroangiopathy
thrombosis usually(TMA), and veno-occlusive
effects lower limbs, disease (VOD).
and clinical presentation in cancer
Venous thrombosis usually effects lower limbs, and clinical presentation in cancer
patients may not differ from those patients without cancer. However, cancer related DVT
patients may not differ from those patients without cancer. However, cancer related DVT
may manifests in several sites (iliocaval, portal or extrahepatic, mesenteric, upper limb
may manifests in several sites (iliocaval, portal or extrahepatic, mesenteric, upper limb
veins, migratory superficial thrombophlebitis) whose singularity should draw attention
veins, migratory superficial thrombophlebitis) whose singularity should draw attention to
to possible
possible unknown
unknown malignancies
malignancies [33].[33]. (Figure
(Figure 2). Specifically,
2). Specifically, the presence
the presence of indwelling
of indwelling
vascular access devices, such as a peripheral inserted central catheter (PICC) or
vascular access devices, such as a peripheral inserted central catheter (PICC) or CVC,
CVC,sub-
subject to periodical anticancer infusions, could represent a source of upper limb and/or su-
ject to periodical anticancer infusions, could represent a source of upper limb and/or
perior vena
superior venacava
cavathrombosis,
thrombosis,due dueto to thrombogenic
thrombogenic catheter material, larger
catheter material, largercatheter
catheter di-
ameter, and
diameter, andgreater
greater number lumens.
number of lumens.

Figure2.2.CT
Figure CTscan
scanininpatients
patientswith hepatocarcinoma.
with hepatocarcinoma.RedRed
arrow: extensive
arrow: thrombosis,
extensive originating
thrombosis, in in
originating
the
thehepatic
hepaticveins
veins(not
(notvisible
visibleinin
these scans),
these invading
scans), thethe
invading right atrium
right through
atrium the inferior
through vena vena
the inferior cava. cava.

5. Treatment
5. Treatment
5.1. Thromboprophylaxis
5.1. Thromboprophylaxis
The use of thromboprophylaxis for primary prevention of VTE is an important clinical
The useissue.
and research of thromboprophylaxis
Extended treatmentfor primary
with prevention
low molecular of VTE
weight is an (LMWH)
heparin importantorclini-
cal and research issue. Extended treatment with low molecular weight heparin
direct oral anticoagulants (DOACs) after discharge of cancer patients decreased VTE events,(LMWH)
orthe
at direct
cost oral anticoagulants
of increased bleeding(DOACs) after
[34]. Several discharge
scores of cancer
have been patients
developed decreased
to assess the risk VTE
events,
of at the cost
cancer-related of increased
VTE. bleeding
A systematic review[34].
andSeveral scores have
meta-analysis beenthe
examined developed to assess
performance
of the Khorana score in predicting VTE in over 34,000 ambulatory patients with various
types of cancer. In the first six-month follow-up, the risk of VTE in patients with a high-risk
Khorana score was 11.0%, which was significantly higher than in those with a low-risk
(5.0%) or intermediate-risk (6.6%) score. These results indicate that the Khorana score may
help clinicians in selecting patients at high risk of VTE for thromboprophylaxis; specifically,
those with a Khorana score ≥ 2 and low bleeding risk [35].
Moreover, Khorana et al. developed a risk model based on five variables assessed
using a cohort study of 2701 cancer patients who were beginning chemotherapy. Patients
with a risk score higher than three (i.e., high risk group) before starting the treatment had a
6.7 to 7.1% risk of developing venous thrombosis [36]. Furthermore, improvements in the
prediction of thrombotic events have been achieved by adding bio-humoral markers (i.e.,
P-selectin > 53.1 ng/mL and D-dimer levels > 1.44 mg/mL) to the Khorana’s risk model.
This expanded model showed a sensitivity of 96% when patients receive a point score of
one, thus reasonably excluding thromboprophylaxis, and a specificity of 98% for those
Biomolecules 2022, 12, 259 6 of 14

at a higher cut off point (score ≥ 5) who may benefit from thromboprophylaxis [33]. A
limitation of this expanded score is the scarce availability of those bio-humoral markers in
daily routine.
In each phase of treatment, from thromboprophylaxis to secondary prevention, adverse
bleeding events represent a challenge in clinical practice. For the International Society
on Thrombosis and Hemostasis, major bleeding is defined as bleeding which caused a
decrease in hemoglobin levels of 2 grams per deciliter or more, led to the transfusion of
two or more units of packed red cells, occurred in a critical site (intracranial, intra-spinal,
intraocular, pericardial, or retroperitoneal bleeding), or contributed to death [37]. Clinically
relevant non-major bleeding (CRNMB) represents a bleeding episode that did not meet the
criteria for major bleeding, but was associated with medical intervention (contact with a
physician, interruption or discontinuation of the assigned treatment, or discomfort in or
impairment of daily life activities [37].
To date, the AVERT and CASSINI trials represent the only trials investigating DOAC
effects in cancer patients who may benefit from thromboprophylaxis. These trials inves-
tigated the efficacy and safety of six months of treatment with apixaban (2.5 mg twice
daily) and rivaroxaban (10 mg once daily), versus placebo, in the prevention of VTE in
high-risk ambulatory patients assessed by the Khorana score [37,38]. In the AVERT trial,
VTE occurred in 4.2% of the apixaban arm and in 10.2% of the placebo arm (Hazard Ratio
(HR) 0.41, 95% CI, 0.26–0.65, p < 0.001), while, in an intention-to-treat analysis, major
bleeding occurred in 3.5% and 1.8% of the apixaban and placebo groups, respectively (HR
2.00, 95% CI, 1.01–3.95, p = 0.046) [33]. In the CASSINI study, the primary endpoint (a
composite of DVT, PE, and death from VTE) showed no difference between the rivaroxaban
group (6.0%) and the placebo group (8.8%), (HR 0.66, 95% CI, 0.40–1.09, p = 0.10) as well as
no difference in the rates of major bleeding, which occurred in 2.0% of the rivaroxaban arm
and 1.0% of the placebo arm (HR 1.96, 95% CI, 0.59–6.49, p = 0.26) [38]. In a cumulative
analysis comparing the results of these two trials, Agnelli showed a significant benefit
of direct oral anticoagulants for the prevention of venous thromboembolism, with a low
incidence of major bleeding [39].

5.2. Acute Treatment of VTE and Secondary Prevention

The selection of patients who have a balanced risk–benefit profile for initiation of
anticoagulation is complex, given individual patient goals and preferences, changing
prognoses of specific cancers, common comorbidities, potential drug–drug interactions,
underweight states, and the competing risks of morbidity and mortality [40].
The choice of which anticoagulation protocol to apply in the presence of active can-
cer should account for potential drug–drug interactions, interference in intestinal tablet
absorption, and the possibility of prompt counteraction, in case of adverse events. The use
of parental LMWH, instead of a Vitamin K antagonist (VKA) or DOAC, can help to reduce
interactions with some anticancer drugs and avoid pharmacokinetic interference due to
chemotherapy-induced nausea and vomiting, as well as increasing the possibility of closer
monitoring [41]. Drug–drug interactions between DOACs and anticancer agents include
cytochrome P450 3A4 (CYP 3A4) and P-glycoprotein (P-gp). These interactions involve
several anticancer drug classes, such as antimitotic microtubule inhibitors, tyrosine kinase
inhibitors, cyclosporine, topoisomerase inhibitors, anthracyclines, and hormone agents [39].
Renal function impairment, including acute and chronic kidney disease, is not uncommon
in cancer patients, and affects both LMWH and DOAC pharmacokinetics. Individual
agents have differing renal clearance rates (dabigatran, 80%; edoxaban, 50%; rivaroxaban,
33%; and apixaban, 27%). Appropriate renal dose adjustment is critical for patients with
renal dysfunction and concomitant DOAC administration; however, LMWH doses should
be adjusted as well [41]. Thrombocytopenia often affects patients with myeloproliferative
malignancy and metastasis of bone marrow. In this setting, anticoagulation should be
strictly monitored when platelet counts are below 50.000 uL [42]. Finally, heparin-induced
Biomolecules 2022, 12, 259 7 of 14

thrombocytopenia represents a common consequence, which can be bypassed by using

fondaparinux.
In the pre-DOAC era, clinical trials in this population compared LMWH monother-
apy to LMWH-bridged warfarin. In the CLOT trial, after initial treatment with LMWH,
672 cancer patients were randomly assigned to dalteparin treatment (200 IU/kg in the first
month, followed by 125 IU/kg) or VKA (International Normalized Ratio (INR) target 2.5)
for six months. The study revealed the superior efficacy of dalteparin compared to vitamin
K antagonists, with no increase in major bleeding events (6 versus 4%, p = 0.27) and a sub-
stantial reduction in recurrent VTE rates observed in the dalteparin-treated group (9 versus
17%; HR 0.48, 95% CI, 0.30–0.77, p = 0.002) [43].
The CATCH study, which compared tinzaparin to warfarin in open label randomiza-
tion, showed that recurrent VTE occurred (in 6 months) in 7.2% of the tinzaparinarm vs.
10.5% of the warfarin arm (0.65 HR, 95% CI, 0.41–1.03; p = 0.07). There were no differences
in major bleeding rates (HR 0.89, 95% CI, 0.40–1.99; p = 0.77) or overall mortality (p = 0.54).
A significant reduction in CRNMB was observed with tinzaparin (p = 0.004) [44].
Recently, the use of DOACs has increased in treatment of VTE, prompting the use of
DOACs in cancer patients with VTE (Table 2). In the Hokusai VTE Cancer study, 1050 cancer
patients with VTE, after 5 days of LMWH treatment, were randomized in an open-label
fashion and assigned to either an edoxaban arm (60 or 30 mg in patients meeting criteria for
dose reduction) or the continuing dalteparin arm. During the 12 month follow-up period,
edoxaban was non-inferior to dalteparin with respect to composite recurrent VTE and
major bleeding rates, which were 12.8% vs. 13.5%, (HR 0.97, 95% CI, 0.70–1.36, p = 0.006).
Recurrent VTE was reduced by edoxaban compared with dalteparin (7.9% vs. 11.3%), but
major bleeding rates increased (6.9% vs. 4.0%), driven by higher bleeding rates in patients
with gastrointestinal cancers. Mortality rates at 12 months were 39.5% (edoxaban arm) and
36.6% (dalteparin arm). This trial shows that edoxaban could be an attractive alternative to
subcutaneous dalteparin for the treatment of the majority of patients with cancer-associated
VTE; however, caution should be advised in subjects with gastrointestinal malignancy due
to an increased risk of major bleeding [45].
In the Select-D Pilot trial, an open-label RCT of 406 patients with cancer (mainly
colorectal, lung, and breast cancer) and VTE, patients were randomly assigned in a 1:1
ratio to a rivaroxaban arm (15 mg twice daily for 3 weeks followed by 20 mg daily) or
dalteparin arm (200 UI/kg once daily for 30 days, followed by 150/UI daily) for 6 months.
Rivaroxaban reduced the risk of recurrent VTE (4% vs. 11%, HR 0.43, 95% CI 0.19–0.99),
but increased the risk of CRNMB (13% vs. 4%, HR 3.76, 95% CI 1.63–8.69) compared to
dalteparin. Overall 6-month survival rates were comparable (75% and 70% for rivaroxaban
and dalteparin, respectively) [46].
Biomolecules 2022, 12, 259 8 of 14

Table 2. Studies investigating the role of DOACs in VTE cancer patients.

Cancer Patients Main results

Study Type of Study Type of Cancer Drugs Follow-Up
Phase Enrolled Excluded Rate of VTE Bleeding
Basal cell and Apixaban vs. Apixaban vs.
Randomized squamous cell Apixaban vs.
AVERT [37] double-blind vs. Thromboprophylaxis 574 6 months Placebo: Placebo:
Placebo carcinoma and acute Placebo 4.2% vs. 10.2%, HR 3.5% vs. 1.8% HR
leukemia. 0.41 (0.26–0.65) 2.00 (1.01–3.95)
Brain (local or
Randomized metastases) and Rivaroxaban vs. Rivaroxaban vs.
CASSINI [38] double-blind vs. Thromboprophylaxis 1080 hematologic Rivaroxaban vs. Placebo: Placebo:
Placebo 6 months 6.0% vs. 8.8% HR 2.0% vs. 1.0% HR
Placebo malignances (except 0.66 (0.40–1.09) 1.96 (0.59–6.49)
lymphoma).

Randomized Basal-cell or Edoxaban vs. Edoxaban vs.

Hokusai-VTE cancer open-label vs. squamous-cell Edoxaban vs. Dalteparin: Dalteparin:
Primary treatment 1050 12 months
[45] carcinoma of the Dalteparin 7.9% vs. 11.3% HR 6.9% vs. 4.0% HR
Dalteparin skin. 0.71 (0.48–1.06) 1.77 (1.03–3.04)

Randomized Basal-cell or Rivaroxaban vs. Rivaroxaban vs.

open-label vs. squamous-cell Rivaroxaban vs. Dalteparin: Dalteparin:
SELECT-D [46] Primary treatment 406 6 months
carcinoma of the Dalteparin 4% vs. 11% HR 0.43 6% vs. 4% HR 1.83
Dalteparin skin. (0.19–0.99) (0.68–4.96)

Randomized Apixaban vs. Apixaban vs.

open-label vs. Apixaban vs. Dalteparin:
ADAM VTE [47] Primary treatment 300 None. 6 months Dalteparin:
Dalteparin Dalteparin 6% vs. 6% HR 0.93 0% vs. 1.4%, HR: NA
(0.43–2.02)
Basal-cell or
squamous-cell
Randomized carcinoma of the Apixaban vs. Apixaban vs.
open-label vs. skin, primary brain Apixaban vs. Dalteparin: Dalteparin:
Caravaggio [48] Primary treatment 1155 6 months
Dalteparin tumor or known Dalteparin 5.6% vs. 7.9% HR 3.8% vs. 4.0%, HR:
intracerebral 0.63 (0.37–1.07) 0.82 (0.40–1.69)
metastases, and
acute leukemia.

Randomized Rivaroxaban vs. Rivaroxaban vs.

CASTA-DIVA [49] open-label vs. Primary treatment 158 None. Rivaroxaban vs. 6 months Dalteparin: 6.4% vs. Dalteparin: 12.2% vs.
Dalteparin 10.1% HR 0.75 9.8% HR 1.27
Dalteparin (0.21–2.66) (0.49–3.26)
DOACs vs. LWMH: DOACs vs. LWMH:
Randomized 6.4% vs. 7.8% HR
CANVAS [50] open-label vs. Primary treatment 811 Acute leukemia. DOACs vs. LWMH 6 months −1.3 5.4% vs. 4.4% HR
LMWH (−4.4–1.7) −1.0 (−1.5–3.6)
Biomolecules 2022, 12, 259 9 of 14

In the AMPLIFY trial, apixaban (10 mg twice daily for 7 days, followed by 5 mg twice
daily) was compared to enoxaparin (1 mg/kg twice daily for at least 5 days) followed
by warfarin (INR for 2–3) for the treatment of acute venous thromboembolism. Of the
5395 patients that were randomized, about 10% had active cancer or history of cancer.
Among patients with active cancer, recurrent VTE occurred in 3.7% and 6.4% of patients in
the apixaban and enoxaparin/warfarin groups, respectively (relative risk (RR) 0.56, 95% CI
0.13–2.37); major bleeding occurred in 2.3% and 5.0% of evaluable patients, respectively
(RR 0.45, 95% CI 0.08–2.46). The result of the subgroup analysis of cancer patients showed
that apixaban may be an interesting option for this category [51].
In the ADAM VTE trial, patients with cancer-associated VTE were randomly assigned
to receive either apixaban (10 mg twice daily for seven days, followed by 5 mg twice
daily) or subcutaneous dalteparin (200 IU/kg once daily for the first month, followed by
150 IU/kg for months 2 through 6) for six months. Recurrent VTE occurred in 0.7% and
6.3% of patients in the apixaban and dalteparin groups, respectively (HR 0.09, 95% CI
0.013–0.780, p = 0.028). Major bleeding was observed in 0% of the apixaban arm vs. 1.4% of
the dalteparin arm (p = 0.138). Apixaban was associated with low major bleeding and VTE
recurrence rates in cancer patients [47].
The Caravaggio trial was a multinational, randomized, investigator-initiated, open-
label, noninferiority trial including 1155 patients with cancer and symptomatic or incidental
proximal DVT or PE. Patients were randomized to receive apixaban (10 mg twice daily
for the first 7 days, followed by 5 mg twice daily) or dalteparin (200 UI/kg once daily for
30 days, followed by 150/UI daily) for 6 months. Recurrent VTE occurred in 5.6% of the
apixaban group and 7.9% of the dalteparin group (HR, 0.63; 95% CI, 0.37–1.07; p < 0.001).
Major bleeding occurred in 3.8% of the apixaban group and 4.0% of the dalteparin group
(HR, 0.82; 95% CI, 0.40 to 1.69; p = 0.60). Apixaban was shown to be noninferior to
subcutaneous dalteparin for the treatment of cancer-associated venous thromboembolism,
without an increased risk of major bleeding [48].
More recently, the CASTA-DIVA study, a randomized open-label non-inferiority trial,
included 158 patients with active cancer who had proximal VTE; patients were assigned
to receive rivaroxaban (15 mg twice daily for 21 days, followed by 20 mg once daily) or
dalteparin (200 UI/kg once daily for 30 days, followed by 150/UI daily) for 3 months.
Recurrent VTE occurred in four patients in the rivaroxaban arm and in six patients in the
dalteparin arm (HR, 0.75; 95% CI, 0.21–2.66; p = 0.13 for noninferiority). Regarding safety
profiles, major bleeding or CRNMB occurred in nine and eight patients in the rivaroxaban
and dalteparin groups, respectively (HR, 1.27; 95% CI, 0.49–3.26) [49].
In addition, the preliminary results of the CANVAS pragmatic randomized trial
showed a non-inferiority of recurrent VTE treatment efficacy in 811 randomized cancer
patients treated with DOACs, vs. LMWH. After 6 months, the VTE rates were similar
between groups (DOACs, 6.4% vs. LMWH, 7.8%) (HR −1.3; 95% CI, −4.4–1.7), with no
differences in major bleeding rates (DOACs, 5.4% vs. LMWH, 4.4%) (HR −1.0 95% CI,
−1.5–3.6) [50].
Moreover, two new trials (COSIMO and CONKO-011) investigated patient-reported
treatment satisfaction with rivaroxaban, as compared to LMWH, for cancer patients with
VTE. CONKO-011 randomized 247 patients into the two arms. Anti-Clot Treatment
Scale (ACTS) Burdens scores, after 4 weeks, were 52.8 versus 51.2 for rivaroxaban vs.
LMWH (p = 0.006), showing improved patient-reported treatment satisfaction with rivarox-
aban [52]. COSIMO was a non-interventional study with 505 subjects enrolled. The results
showed patients’ treatment satisfaction following a planned switch from traditional therapy
(LMWH/VKA/fondaparinux) to rivaroxaban in VTE cancer patients. Mean ACTS Burdens
scores were higher until 6 months after the beginning of rivaroxaban therapy, compared
to baseline (55.6 vs. 51.8, respectively; p < 0.0001 at 4 weeks), confirming improvement of
patient-reported anticoagulation burden [53].
The International Society on Thrombosis and Hemostasis (ISTH) and National Com-
prehensive Cancer Network (NCCN) 2018 guidelines recommend LMWH as the standard
 Biomolecules 2022, 12, 259 10 of 14

of care in treating cancer-associated VTE, with fondaparinux and unfractionated heparin as

alternative treatment options, compared to oral anticoagulant treatment with warfarin [54].
The 2019 ASCO Clinical Practice Guideline Update underscored the importance of
risk stratification for VTE risk, as well as the importance of effective treatment to reduce
the risk of VTE recurrence and mortality [55].
It stands to reason that the occurrence of cancer heavily affects all three phases of the an-
Biomolecules 2022, 12, 259 ticoagulation management of DVT; initial management (consisting of the first 5 to1021ofdays), 13

primary treatment (the 3 to 6 months following initial management), and secondary pre-
vention (the duration of which depend on VTE recurrency), as classified by the recent
guidelines
Anticoagulantfor management
treatment DOACs of venous thromboembolism
provide a reasonable [55].
alternative to LMWH in the
treatment Anticoagulant
of VTE in cancer treatment
patients;DOACs provide
however, a reasonable
particular alternative
care should be takento LMWH
to monitorin the
treatment
bleeding of VTE
events, in cancer
especially thosepatients;
that arehowever, particular
gastrointestinal care should
or urinary [56].be taken to monitor
bleeding events,question
An unsolved especiallythatthose that is
remains arethe
gastrointestinal
optimal duration or urinary [56].
of anticoagulant therapy
in cancer An unsolved
patients. question
After that phase
the acute remains of is
VTEthe(3–6
optimal duration
months), it is of anticoagulant
reasonable therapy
to extend
the anticoagulant regimen for high-risk patients until 12 months or longer. Indeed, the the
in cancer patients. After the acute phase of VTE (3–6 months), it is reasonable to extend
anticoagulant
trials investigating regimen for high-riskofpatients
the management secondaryuntilprevention
12 monthsafter or longer.
venous Indeed, the trials
thrombotic
investigating the management of secondary prevention
events are the RE-MEDY, RE-SONATE, EINSTEIN-EXT, EINSTEN-CHOISE, and Am- after venous thrombotic events
are the trials,
plify-EXT RE-MEDY, whichRE-SONATE,
evaluate theEINSTEIN-EXT,
efficacy of DOACs EINSTEN-CHOISE,
in preventing recurrent and Amplify-EXT
venous
trials, which
thrombosis afterevaluate
6 months. theInefficacy of DOACs
the RE-MEDY andinRE-SONATE
preventing recurrent venous thrombosis
trials, dabigatran vs. war-
after
farin 6 months.
or placebo, In the RE-MEDY
respectively, showed and RE-SONATE
a reduction trials, VTE
of recurrent dabigatran vs. warfarin
with similar rates of or
placebo, respectively, showed a reduction of recurrent
major bleeding [57]. In the EISTEIN-EXT and EINSTEN-CHOISE trials, rivaroxaban VTE with similar rates of re-
major
duced the risk of recurrent VTE without a difference in major bleeding rates compared tothe
bleeding [57]. In the EISTEIN-EXT and EINSTEN-CHOISE trials, rivaroxaban reduced
risk oforrecurrent
placebo VTE withoutin
aspirin, respectively; a difference in majortrial,
the Amplify-EXT bleeding ratesshowed
apixaban compared thetosame
placebo
re- or
aspirin, respectively; in the Amplify-EXT trial, apixaban showed
sults versus placebo [57]. However, active malignancies were considered an exclusion cri- the same results versus
placebo
terion [57].
in these However,
trials; therefore,active malignancies
these results cannot were considered an
be extrapolated to exclusion
the oncologic criterion
pop- in
ulation. A dedicated study on this issue should be conducted to acquire these protocols in A
these trials; therefore, these results cannot be extrapolated to the oncologic population.
dedicated
clinical practice study on this
(Figure 3). issue should be conducted to acquire these protocols in clinical
practice (Figure 3).

Figure 3. Strategies for anticoagulation management in patients with active malignancies. UFH,
Figure 3. Strategies for anticoagulation management in patients with active malignancies. UFH, un-
unfractionated
fractionated heparin;
heparin; LMWH, LMWH, low molecular
low molecular weightweight heparin;
heparin; Od,daily;
Od, once once daily; Bid,
Bid, bis in bis
die.in die.
6. Prognosis
6. Prognosis
The concomitant presence of cancer and a thromboembolic event reduces survival
The concomitant
rates fivefold, whenpresence
compared of cancer and a thromboembolic
to a thrombotic event alone, atevent
1 yearreduces
[13]. Onsurvival
the other
rates
hand, the survival rate of patients with cancer and venous thrombosis is more thanother
fivefold, when compared to a thrombotic event alone, at 1 year [13]. On the halved
hand,
at 1the survival
year rate of patients
if compared to cancerwith cancer and
populations venousvenous
without thrombosis is more than
thrombosis, after halved
matching
at 1for
year if gender,
age, compared to of
type cancer populations
cancer, without
and year of venous
diagnosis [58]. thrombosis, afterthrombosis
Indeed, venous matching is
for age, gender, type of cancer, and year of diagnosis [58]. Indeed, venous thrombosis is a
significant prognosticator at 1 year for all cancer types, in a large cohort study of more
than 230 thousand cancer patients, with and without thrombotic events [21]. Even though
the specific weight of thrombotic events alone on mortality rates in cancer populations is
difficult to estimate, thrombotic events are the second most common cause of death in
Biomolecules 2022, 12, 259 11 of 14

a significant prognosticator at 1 year for all cancer types, in a large cohort study of more
than 230 thousand cancer patients, with and without thrombotic events [21]. Even though
the specific weight of thrombotic events alone on mortality rates in cancer populations
is difficult to estimate, thrombotic events are the second most common cause of death in
patients with cancer, after cancer progression itself [59].

7. Conclusions
Cancer-related venous thrombotic events are a common clinical manifestation during
the course of disease. The pathogenesis of cancer-induced VTE is multifactorial, and in-
volves several pathways, including direct coagulation pathway activation, the induction
of inflammatory responses, the inhibition of fibrinolytic activity, and tumor cell-induced
platelet aggregation. The right choice of treatment, between anticoagulation strategy,
thrombo-hemorrhagic risk management, and patients’ comorbidities, represents a chal-
lenge for physicians. An accurate risk stratification, to select patients at higher risk for
thrombotic events who would benefit from thromboprophylaxis, should be encouraged.
Early identification and treatment of this complication is particularly relevant in the onco-
hematologic setting, given the substantial impact of venous thrombotic events on morbidity
and mortality. The “one fits all” choice of LMWH is giving way to DOAC strategy, in
specific settings. Indeed, despite some evidence of increased risk of major bleeding, DOACs
are an attractive alternative to LMWH in the treatment of VTE in cancer patients, especially
those without drug interactions, and those with significantly impaired renal function. The
recent Sars-CoV2 pandemic has drawn attention to the management of venous and arterial
thromboembolism, an issue that is even more compelling in patients affected by both cancer
and COVID 19, who require intensive care [60]. The large amount of multiple connections
between the thrombotic pathway and cancer growth needs to be furtherly elucidated, today
more than ever, in order to provide accurate prognostic scores and data-driven decisions
for this vulnerable population.

Author Contributions: Conceptualization, writing—original draft, M.E.C. and C.S.; investigation,

M.A.; resources, M.P., G.E.M. and G.G.; supervision, A.F.; writing—review and editing, R.P.; formal
analysis, F.I.; supervision, M.C.; writing—review and editing, G.E. All authors have read and agreed
to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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