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Arteriosclerosis, Thrombosis, and Vascular Biology

ATVB IN FOCUS:
Thromboinflammation and Infection
Series Editors: Katsue Suzuki-Inoue and Elizabeth Gardiner

Updates in the Incidence, Pathogenesis,


and Management of Cancer and Venous
Thromboembolism
Laura Girardi , Tzu-Fei Wang , Walter Ageno , Marc Carrier

ABSTRACT: Patients with cancer are at higher risk of developing venous thromboembolism (VTE) compared with the general
population. This elevated risk is due to several risk factors and multiple, overlapping thrombotic and hemostatic pathophysiological
pathways that are specific to this patient population. Hence, the management of cancer-associated VTE can be challenging for
clinicians. Patients with cancer-associated VTE are at higher risk of both recurrent events despite anticoagulation and bleeding
complications due to the anticoagulant regimens. Direct oral anticoagulants have recently been shown to be effective, safe, and
more convenient than parenteral low-molecular-weight heparin for the management of cancer-associated VTE. Despite these
recent advances in anticoagulant therapy, many unmet needs remain in these patients (increased risk of bleeding with specific
cancer types, drug-drug interactions, liver dysfunction). Factor XI inhibitors are currently being assessed for the management of
cancer-associated VTE and may help clinicians address these important knowledge gaps.
GRAPHIC ABSTRACT: A graphic abstract is available for this article.
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Key Words: anticoagulants ◼ hemorrhage ◼ neoplasms ◼ venous thromboembolism ◼ venous thrombosis

P
atients with cancer are known to be at high risk Please see www.ahajournals.org/atvb/atvb-focus for all
of both arterial and venous thromboembolic (VTE) articles published in this series.
events, which is associated with significant mor-
bidity and previously reported as the second leading INCIDENCE AND RISK FACTORS FOR
cause of death in this patient population.1 VTE is the
most common thrombotic complication in patients with
CANCER-ASSOCIATED VTE
cancer.2 The risk of developing VTE in patients with Cancer-associated VTE (CAT), which mainly includes VTE
cancer is increased by 12-fold compared with patients with upper- or lower-extremity deep vein thrombosis and
without cancer.3 It is estimated that up to 20% of pulmonary embolism, is a common complication among
patients with cancer will be affected by VTE, with the patients with cancer.5 The 6-month VTE risk in patients
highest risk periods associated with hospitalizations with cancer is up to 12-fold higher than in the general
and the development of metastatic disease.4 The pur- population and up to 23-fold higher in patients with can-
pose of this narrative review is to summarize the inci- cer receiving chemotherapy or targeted therapy.3 Further-
dence and clinical significance of VTE in patients with more, the cumulative incidence of CAT is increasing over
cancer, outline the importance of the pathogenesis, time, from 1.0% in 1997 to 3.4% in 2017, likely due to the
review the evidence on the management of VTE and improved survival of patients with cancer and the increased
highlight unmet needs that will drive further research use of computed tomography scans leading to increased
in this patient population. rates of incidental pulmonary embolism diagnoses.3

Correspondence to: Marc Carrier, MD, MSc, Thrombosis Program, Department of Medicine, Division of Hematology, The Ottawa Hospital General Campus, University of
Ottawa, 501 Smyth Rd, Box 201A, Ottawa, Ontario K1H 8L6, Canada. Email mcarrier@toh.ca
For Sources of Funding and Disclosures, see page 829.
© 2023 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol is available at www.ahajournals.org/journal/atvb

824   June 2023 Arterioscler Thromb Vasc Biol. 2023;43:824–831. DOI: 10.1161/ATVBAHA.123.318779
Girardi et al Cancer-Associated Thrombosis

Nonstandard Abbreviations and Acronyms Highlights

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CAT  cancer-associated venous • Patients with cancer are at higher risk of developing
thromboembolism venous thromboembolism.
DOAC direct oral anticoagulant • The management of cancer-associated thrombosis
IL interleukin is challenging due to both higher risk of thrombotic
recurrences and bleeding complications compared
LMWH low-molecular-weight heparin
with general population.
PAI-1 plasminogen activator inhibitor 1 • Pathophysiology of cancer-associated thrombosis is
RR relative risk complex but can also be a source of identifiable bio-
sCLEC-2 soluble C-type lectin-like receptor 2 markers for both prevention and precision therapies.
TF tissue factor
TNF tumor necrosis factor
VTE venous thromboembolism patients with cancer have a lower 1-year incidence of VTE
complication compared with White or Black patients.20
Furthermore, concomitant prothrombotic genetic risk
A large observational cohort study published in 2017 factors such as factor V Leiden and non-O blood types
has estimated the incidence of first and recurrent VTE are also associated with CAT events.21 Chemotherapy is
among patients with active cancer to be 5.8 (95% CI, 5.7– also an important risk factor for CAT.21 Cisplatin-based
6.0) and 9.6 (95% CI, 8.8–10.4) per 100 person-years, chemotherapy has been widely reported to increase
respectively.6 The rates of recurrent events were indepen- the risk of CAT.22 Many other systematic chemotherapy
dent of the type of the index event (ie, pulmonary embo- agents (including L-asparaginase, thalidomide, lenalido-
lism or deep vein thrombosis). The mortality risk after VTE mide) have been shown to increase the risk of arterial
was also considerable, with most deaths (64.5%) occur- and venous thrombosis.23,24 Targeted therapies including
ring within the first year following the CAT diagnosis. antiangiogenic agents (eg, bevacizumab) and immune
The pathogenesis of CAT is multifactorial, and mul- checkpoint inhibitors have also been shown to increase
tiple risk factors have been identified, including cancer- the risk of thromboembolism.25,26 It remains unclear
associated risk factors, therapy-related risk factors, whether the underlying risk of thrombotic complication in
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patient-related risk factors, and the presence of certain patients receiving targeted therapies is higher than for
biomarkers.7,8 Cancer-related risk factors include can- those receiving chemotherapy.26 In addition to chemo-
cer site, stage, and time since cancer diagnosis.5,9–12 therapy, other cancer and supportive treatment modalities
The highest risk is reported to be associated with pan- are proved to substantially increase the thrombotic poten-
creas, brain, stomach, lung, and ovarian cancers.9,13–15 In tial. Surgery, hormonal therapy, erythropoiesis-stimulating
patients with pancreas and brain cancers, the incidences agents, blood transfusions, and central venous catheters
of VTE were reported to be as high as 59 and 48 per are all reported to be associated with an increased risk.1,7
1000 person-years, respectively.11 Patients with breast Although VTE incidence varies per cancer type and
and prostate cancers have lower incidences with only 10 stage, it seems to be associated with an increased risk of
per 1000 person-years for both tumor types.11 This was mortality independent of the cancer characteristics.16,27
confirmed in an observational cohort study using the Cali- A population-based case-control study has reported that
fornia Cancer Registry, which also reported that the high- the 1-year survival was significantly lower in patients
est 2-year cumulative incidence of VTE was in patients with CAT compared with patients with cancer without
with cancers of the pancreas (12%), brain (12%), ova- VTE (12% versus 36%).27 Another observational study
ries (9.3%), and lung (7.6%).16 Many studies have dem- has also reported a significant increase in mortality (haz-
onstrated that metastatic disease was an important risk ard ratio, 1.6–4.2; P<0.01) in patients with different
factor for CAT.13,17 The presence of metastatic disease tumor types and CAT after adjusting for age, sex, can-
has been reported to be associated with a 1.9 increased cer stage, and additional comorbidities.13 The heightened
risk (relative risk [RR], 1.9 [95% CI, 1.6–2.3]) of VTE in underlying risk of death might be due to fatal pulmonary
patients with different tumor types.17 embolism, major bleeding complications associated with
Patient- and treatment-related factors also play impor- therapeutic anticoagulation, and is likely a measure of
tant roles in the development of CAT. Several traditional biological aggressiveness of the cancer.27,28
risk factors for VTE have been identified in many patients
with cancer such as older age,6 ethnicity,18 history or
family history of VTE,19 comorbidities (eg, renal failure, PATHOGENESIS OF CAT
respiratory disease, acute infection, and obesity14), and Multiple overlapping and interacting pathways explain the
prolonged immobility.12 For example, Hispanic and Asian increased incidence of arterial and venous thrombosis in

Arterioscler Thromb Vasc Biol. 2023;43:824–831. DOI: 10.1161/ATVBAHA.123.318779 June 2023   825
Girardi et al Cancer-Associated Thrombosis

patients with cancers. The pathogenesis of CAT seems extracellular traps can directly activate platelets and lead
to be different compared with the development of VTE in to the further thrombin generation.40 Finally, cytokine pro-
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patients without cancer. The underlying mechanisms of duction from cancer cells (TNF [tumor necrosis factor]-α,
CAT include activation of the coagulation, dysregulation IL-1β, IL-6, IL-17), aggregated platelets, and activated
of fibrinolytic systems, inflammation, and cytokine pro- leukocytes also contributes to endothelium damage and
duction (Figure 1).29,30 thrombus formation (Figure 1). All these overlapping
TF (tissue factor) seems to be an important trigger of pathways can also lead to the development of dissemi-
the hypercoagulability associated with CAT.31 TF is a pro- nated intravascular coagulation, which can be another
coagulant protein that initiates the extrinsic pathway of important contributor to thromboembolic complications.
the coagulation cascade by creating complexes with fac- The current data suggest that there may be cancer type–
tor VII, which will promote the activation of factor X and specific pathways of VTE.41 Therefore, the understanding
the formation of factor Xa. Tumor cells can constitutively of the pathogenesis of CAT is important and can lead to
express TF and release extracellular vesicles expressing the identification of biomarkers helping clinicians to iden-
TF leading to thrombin and fibrin formation.32–34 Multiple tify patients with cancer at high risk of VTE and poten-
studies have reported elevated plasma level of TF in tially eligible for primary prevention42–44 and those with
patients with different cancer types (eg, pancreas, brain, CAT at high risk of recurrent events.45 For example, a
gastric).1 The fibrinolytic system is also altered in patients correlation between sCLEC-2 (soluble C-type lectin-like
with cancer. PAI-1 (plasminogen activator inhibitor 1) is a receptor 2) levels and podoplanin expression has recently
serine protease that inhibits tissue plasminogen activator been established in patients with high-grade gliomas.42
and urokinase promoting the formation and deposition A relevant relationship between sCLEC-2 levels and
of fibrin.1 Elevated plasma level of PAI-1 can be found the occurrence of CAT was demonstrated among these
in different tumor types (eg, brain, lung, pancreas).35,36 patients suggesting that podoplanin could be a potential
Furthermore, cancer cells are capable of secreting marker to predict CAT in this patient population.42
platelet-activating factors (eg, adenosine diphosphate,
thromboxane A2, CD40 ligand).1,37,38 In addition, tumor
cytokines can activate endothelial cells. Moreover, neu- MANAGEMENT OF CAT
trophil extracellular traps formed from activated neutro- Given the overlapping altered thrombotic and hemo-
phils are an important mediator in the development of static pathways in patients with cancer, the management
CAT. Stimulation of neutrophils (eg, IL [interleukin]-8, of CAT can be challenging. The risk of recurrent VTE
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IL-1β, IL-17, activated endothelial cells) can induce despite appropriate anticoagulant therapy and the risk of
NETosis, which is used as a scaffold for platelets and bleeding on anticoagulation are higher among patients
other procoagulants.39 The histones present in neutrophil with cancer compared with those without cancer.28 This

Figure 1. Multiple mechanisms in


cancer-associated thrombosis.
FVII indicates factor VII; FXa, factor Xa; IL,
interleukin; NETs, neutrophil extracellular
traps; PAI-1, plasminogen activator
inhibitor 1; TF, tissue factor; TNFα,
tumor necrosis factor alpha; and TxA2,
thromboxane A2.

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Girardi et al Cancer-Associated Thrombosis

leads to an increase in the rates of hospitalization and day). In addition, DOAC is associated with a higher risk
health care costs and a significant decrease in the quality of clinically relevant nonmajor bleeding compared with

ATVB IN FOCUS - T
of life in these patients.43 Furthermore, multiple qualita- LMWH in patients with CAT. These events seem to be
tive studies have demonstrated that CAT is traumatic and more commonly related to gastrointestinal bleeding, epi-
distressing for patients and their families, highlighting staxis, hematuria, or abnormal uterine bleeding. Given the
the lack of support and awareness for its diagnosis and lack of direct head-to-head comparisons and significant
treatment.44 Hence, it is imperative to urgently start an heterogeneity among the clinical trials, it is not possible
effective and safe anticoagulant regimen in patients with to recommend one DOAC over another. Based on these
CAT to avoid any potential adverse events. findings, recent guidelines mostly suggest that either
Several anticoagulant regimens, including vitamin K apixaban, edoxaban, rivaroxaban, or LMWH can be used
antagonists, low-molecular-weight heparins (LMWHs), for the management of CAT (Table).58–63 Anticoagulation
and direct oral anticoagulants (DOACs), have been eval- should be tailored based on patient characteristics and
uated for the management of CAT. LMWH monotherapy preferences and should be adapted and reassessed on a
has been the standard of care for the management of regular basis, as the patient’s cancer status and manage-
CAT for many years.46,47 A meta-analysis has reported ment change over time (Figure 2).64
that the use of LMWH (compared with vitamin K antago-
nists) was associated with a significant reduction in the
risk of recurrent events (RR, 0.58 [95% CI, 0.43–0.77]) FUTURE
without a significant increase in the risk of major bleed- Despite the multiple anticoagulation regimens available
ing (RR, 1.09 [95% CI, 0.55–2.12]).48 Despite the fact to manage CAT, there are still numerous unmet needs.
that LMWHs have several advantages over vitamin K Treatment with LMWH requires once- or twice-daily
antagonists (fewer drug-drug interactions, dependable subcutaneous injection and seems to be associated
pharmacokinetics, shorter half-life), its need for once- or with shorter persistence compared with oral anticoagu-
twice-daily injections and higher costs are associated lants.49 Although DOACs may be an attractive alterna-
with lower adherence and persistence by patients.49 tive to LMWH, they are associated with higher risk of
DOACs have become a valid, effective, safe, and more bleeding complications (major and clinically relevant
convenient alternative for the management of acute VTE nonmajor bleeding) in specific tumor types (eg, unre-
in the general population. DOACs are now recommended sected gastrointestinal and genitourinary cancers),64
as first-line therapy in this setting as their risk-benefit and there are little data supporting their use in patients
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ratio is favorable compared with vitamin K antago- with additional risk factors for bleeding (eg, primary brain
nists.50,51 Based on these findings and on their promising tumor, thrombocytopenia), for whom adjusted doses of
features, DOACs and, more specifically, the direct fac- LMWHs remain the treatment of choice. Furthermore,
tor Xa inhibitors apixaban, edoxaban, and rivaroxaban the use of DOACs should be avoided in patients taking
have been compared with LMWH for the management other medications (including anticancer and supportive
of CAT.52–55 A meta-analysis combining the results of therapies) with possible drug-drug interactions.65 All
all randomized controlled trials has shown that patients DOACs are substrates of P-glycoprotein, and apixaban
receiving DOACs had significantly lower risk of recur- and rivaroxaban are also substrates of CYP3A4. There-
rent VTE events (RR, 0.67 [95% CI, 0.52–0.84]) without fore, treatments that affect P-glycoprotein or CYP3A4
a significant increased major bleeding events (RR, 1.17 metabolism have the potential to interact with DOACs
[95% CI, 0.82–1.67]) but with a significant increase in and should preferentially be avoided. Finally, renal and
clinically relevant nonmajor bleeding (RR, 1.66 [95% CI, liver dysfunction are common in patients with cancer
1.31–2.09]) when compared with LMWH.56 Randomized and can lead to higher plasma concentration of DOACs
controlled trials comparing edoxaban and rivaroxaban and bleeding concerns. Hence, new anticoagulants that
with LMWH have reported a higher risk of major bleed- are safe and effective for the management of CAT but
ing episodes in patients receiving DOACs.53,55 These that are also addressing these unmet needs are desper-
findings seem to be due to an excess of gastrointesti- ately needed to optimize the care of patients with cancer
nal bleedings occurring mostly in patients with gastro- and VTE (Figure 2).64
intestinal cancers.57 A different result is shown by the As mentioned previously, multiple mechanisms lead
trial that compared apixaban to LMWH, which showed to activation of the coagulation cascade and excess
that DOAC was associated with a similar risk of gastro- thrombin generation in patients with cancer (Figure 1).
intestinal bleeding when compared with LMWH (hazard Furthermore, extracellular vesicles from various cancer
ratio, 1.05 [95% CI, 0.44–2.50]).52 The reasons for the cell lines have been shown to activate FXII and initiate
discrepancy in the risk of gastrointestinal bleeding are the intrinsic pathway.66 Thrombin and factor XIIa activate
unclear and may be related to heterogeneity in the base- factor XI, leading to the further amplification of the coag-
line characteristics of included patients or to the differ- ulation cascade. Hence, inhibition of factor XI maybe
ences in the DOAC properties (eg, once versus twice a be an innovative and effective pathway to address the

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Girardi et al Cancer-Associated Thrombosis

Table. Summary of the Clinical Practice Guidelines Recommendations for the Management of Cancer-Associated Thrombosis

Recommendation
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Guideline Initial treatment Long-term treatment


ASCO LMWH, UFH, fondaparinux, or rivaroxaban. LMWH, edoxaban, or rivaroxaban for ≥6 mo is preferred.
(2019)58
For patients initiating treatment with parenteral anticoagulation, LMWH is
preferred over UFH.
ASH DOAC (apixaban or rivaroxaban) or LMWH should be used for initial treat- For patients requiring long-term anticoagulation (>6 mo), DOACs
(2021)59 ment of VTE for patients with cancer. or LMWH.
For the short-term treatment of VTE (3–6 mo), DOAC (apixaban, edoxaban,
or rivaroxaban) is recommended over LMWH and over VKA.
DOACs should be used carefully for patients with GI cancers.
ESMO LMWH, UFH, fondaparinux, apixaban, and rivaroxaban are recommended Long-term anticoagulation for at least 6 mo includes LMWH, apix-
(2022)60 treatments for the acute phase. aban, edoxaban, or rivaroxaban, which are preferred over VKAs.
LMWH is preferred over UFH or fondaparinux.
UFH may be considered in patients with severe renal impairment (defined
as CrCl <30 mL/min).
ITAC LMWH is recommended when CrCl is ≥30 mL/min. LMWH or DOACs should be used for a minimum of 6 mo.
(2022)61
For patients without high risk of GI or GU bleeding, rivaroxaban, apixaban, After 6 mo, therapy should be based on individual evaluation.
or edoxaban can also be used when CrCl is ≥30 mL/min.
UFH can also be used when LMWH or DOACs are contraindicated.
NCCN Apixaban, edoxaban, or rivaroxaban is preferred for patients without gastric
(2020)62 or gastroesophageal lesions.
LMWH is preferred for patients with gastric or gastroesophageal lesions.

ASCO indicates American Society of Clinical Oncology; ASH, American Society of Hematology; CrCl, creatinine clearance; DOAC, direct oral anticoagulant; ESMO,
European Society for Medical Oncology; GI, gastrointestinal; GU, genitourinary; ITAC, International Initiative on Thrombosis and Cancer; LMWH, low-molecular-weight
heparin; NCCN, National Comprehensive Cancer Network; UFH, unfractionated heparin; VKA, vitamin K antagonist; and VTE, venous thromboembolism.

current unmet needs for the management of CAT. Pre- Four phase II randomized controlled trials have evalu-
vious studies have shown that factor XI deficiency (ie, ated different factor XI inhibitors and found them to be
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hemophilia C) or inhibition of factor XI seems to protect noninferior or superior to enoxaparin for the prevention of
against thrombotic complications with little or no bleed- VTE after knee replacement surgery without increasing
ing.67,68 However, patients with elevated plasma factor XI bleeding risks.72–75 One of the factor XI inhibitors, abel-
levels were found to be at higher risk of thromboembo- acimab, is a monoclonal antibody that binds factor XI and
lism.69 The role of factor XI in the contact system and locks it in its inactive precursor form, preventing its activa-
the intrinsic pathway appears to be essential for throm- tion by factor XIIa or thrombin. Administration of abelaci-
bosis formation, stabilization, and growth but not hemo- mab yields rapid and dose-dependent factor XI inhibition.
stasis.70,71 Hence, factor XI inhibitors could potentially be Because the half-life of abelacimab is 20 days, this drug
effective anticoagulants to manage VTE without bleed- can be administered monthly.70 Given that it is adminis-
ing complications. tered parenterally, it is not dependent on P-glycoprotein

Figure 2. Treatment algorithm in


cancer-associated thrombosis (CAT).
DOAC indicates direct oral anticoagulant;
GI, gastrointestinal; GU, genitourinary;
and LMWH, low-molecular-weight heparin.

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Girardi et al Cancer-Associated Thrombosis

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ATVB IN FOCUS - T
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ARTICLE INFORMATION Marosi C, Zielinski C, Pabinger I. High factor VIII levels independently pre-
Received March 1, 2023; accepted April 17, 2023. dict venous thromboembolism in cancer patients: the cancer and throm-
bosis study. Arterioscler Thromb Vasc Biol. 2009;29:2176–2181. doi:
Affiliations 10.1161/ATVBAHA.109.190827
Department of Medicine and Surgery, University of Insubria, Varese, Italy (L.G., 16. Brunson AM, Keegan THM, Mahajan A, White RH, Wun T. Cancer associ-
W.A.). Department of Medicine, Ottawa Hospital Research Institute, University of ated venous thromboembolism: incidence and impact on survival. Thromb
Ottawa, Ontario, Canada (T.-F.W., M.C.). Res. 2018;164:S178–S179. doi: 10.1016/j.thromres.2018.02.012
17. Blom JW, Vanderschoot JPM, Oostindiër MJ, Osanto S, van der Meer FJM,
Sources of Funding Rosendaal FR. Incidence of venous thrombosis in a large cohort of 66,329
M. Carrier is the recipient of a Tier 1 Research Chair in Cancer and Thrombosis cancer patients: results of a record linkage study. J Thromb Haemost.
from the Department and Faculty of Medicine at the University of Ottawa. 2006;4:529–535. doi: 10.1111/j.1538-7836.2006.01804.x
18. White RH, Zhou H, Murin S, Harvey D. Effect of ethnicity and gender on the
Disclosures incidence of venous thromboembolism in a diverse population in California in
T.-F. Wang reports advisory board honoraria from Servier and Valeo and research 1996. Thromb Haemost. 2005;93:298–305. doi: 10.1160/TH04-08-0506
funding to the institution from Leo Pharma. W. Ageno reports advisory board hon- 19. Zöller B, Palmer K, Li X, Sundquist J, Sundquist K. Family history of venous
oraria from Bayer, Boehringer Inghelheim, Daiichi Sankyo, Bristol-Myers Squibb thromboembolism and risk of hospitalized thromboembolism in cancer
(BMS)/Pfizer, Sanofi, and Portola and reports research funding and personal patients: a nationwide family study. Thromb Res. 2015;136:573–581. doi:
fees from Bayer and personal fees from BMS/Pfizer, Daiichi Sankyo, Sanofi, As- 10.1016/j.thromres.2015.07.004
pen, Janssen, and Portola, outside the submitted work. M. Carrier has received 20. da Costa WL, Guffey D, Oluyomi A, Bandyo R, Rosales O, Wallace CD,
research funding from BMS, Pfizer, and Leo Pharma and honoraria from Bayer, Granada C, Riaz N, Fitzgerald M, Garcia DA, et al. Patterns of venous throm-
Pfizer, BMS, Servier, and Leo Pharma. The other author reports no conflicts. boembolism risk, treatment, and outcomes among patients with cancer from
uninsured and vulnerable populations. Am J Hematol. 2022;97:1044–1054.
doi: 10.1002/ajh.26623
21. Pabinger I, Ay C, Dunkler D, Thaler J, Reitter E-M, Marosi C,
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