Cancer-associated Thromboembolism Research Articles

Venous thromboembolism treatment in patients with cancer: reflections on an evolving landscape

Cancer is a leading cause of morbidity and mortality worldwide. It is also one of the strongest risk factors for venous thromboembolism (VTE), reported in approximately 20% of all cases of VTE diagnosed. The thrombotic effect of cancer and its treatments, however, is highly variable among patients and changes over the course of their cancer. Anticoagulant therapy remains the cornerstone of VTE treatment, but it is associated with a substantial rate of VTE recurrence and the potential for serious bleeding. The risk of bleeding in patients with cancer is also dependent on the cancer type and its treatments, often revealing underlying tumor invasion of mucosal or parenchymal tissues, and treatment complications such as thrombocytopenia or coagulopathy. Over the past few decades, efforts to improve the efficacy and safety of anticoagulant therapy for the treatment and prevention of cancer-associated thromboembolism have resulted in changes in the standard of practice. This evolution has been made possible largely through the development of new anticoagulants. This review will reflect on the major advances in the treatment of cancer-associated thrombosis and offer insights on how to address unmet needs in this field.

Efficacy and Safety Outcomes in Patients with Cancer-Associated Thromboembolism Treated with Tinzaparin According to the Tumor Site: Meta-Analysis of Prospective Studies Involving 1413 Individual Patients' Data

Introduction DOAC (direct oral anticoagulant) and LMWH (Low Molecular Weight Heparin) are recommended by international guidelines as first line therapy in patients with CAT (Cancer Associated Thrombosis), but the risk of venous thromboembolic recurrence (rVTE) and the risk of major bleeding (MB) remains high. Several scores have attempted to predict these risks with disappointing results, probably because of heterogeneous treatments and small sample sizes representing various tumor sites. We conduct a meta-analysis on individual patient level data to report the rate of rVTE and MB by 6 months according to site of cancer from prospective studies involving CAT patients on tinzaparin. Methods The meta-analysis is based on individual patient data from prospective studies that included patients with CAT treated with tinzaparin who were followed for 6 months (PROSPERO registration CRD42019119907). Eligible studies must include controlled data and a central decision for study outcomes. Main outcomes were cumulative incidence of rVTE and MB at 6 months. Time-to-event outcomes were estimated using competing risk regression (Fine and Gray's method with death as competing risk). Cumulative incidences were presented with corresponding 95% confidence interval (95% CI). Time-to-event outcomes were estimated using competing risk regression (Fine and Gray's method with death as competing risk). Cumulative incidences were presented with corresponding 95% confidence interval (95% CI). Results Three prospective cohort studies (AXA - NCT02898051, 308 patients; PREDICARE - NCT03099031, 409 patients (1); TICAT - NCT01164046, 247 patients (2) and the Tinzaparin arm of the CATCH study (NCT01130025, 449 patients (3)) were included. A total of 1413 patients (median age 65.0 [IQR 56.0-73.5], 51.9% female) were included in the meta-analysis. Cancers were mostly solid tumors (91.7%); primary sites were gastrointestinal (27.0%), lung (18.0%), breast (11.8%), genitourinary (14.4%); ECOG performance status was ≥ 2 for 30.2%. At 6 months, 74 patients experienced a rVTE, for a cumulative incidence of 5.4% [95% CI: 4.3%; 6.7%], while 47 patients had a MB, for a cumulative incidence of 3.4% [95% CI: 2.6%; 4.6%]. Clinical outcomes according to the type of cancer are summarized in the Table. rVTE cumulative incidence varied from 0.6 to 8.5% and rVTE occurred more frequently in patients with genitourinary, lung and gynecological cancers, while MB cumulative incidence ranged from 2.1% to 4.2% across different cancer sites (Table). Overall mortality ranged from less than 18% (breast and hematological cancers) to 45.2% (lung cancer) within 6 months of the index VTE. Conclusion In CAT patients receiving tinzaparin for up to 6 months, rVTE and MB vary according to tumor site. The CAT entity is not sufficient to describe a situation at risk of recurrence or bleeding for patient management.

Management of cancer-associated thromboembolism: Introduction

Management of cancer-associated thromboembolism: Introduction

Does the diagnostic timing of cancer-associated thromboembolism influence the survival outcome in ovarian cancer patients?

Efforts were made to explore the influence of diagnostic timing for cancer-associated thromboembolic events on survival of ovarian cancer patients. We reviewed the medical records of 75 ovarian cancer patients with thromboembolism and evaluated the prognostic factors affecting disease-free survival and overall survival. These 75 patients were classified into two categories by the diagnostic timing of the thromboembolism, during (33 cases) and after (42 cases) initial diagnosis of ovarian cancer groups. The diagnostic timing of thromboembolism was not related to disease-free survival or overall survival of the studied population. Advanced disease stage, clear cell histology, interval debulking surgery, no recurrence/persistence of ovarian cancer, and patients treated with anticoagulant(s) treatment >3 months were associated with the disease-free survival. Advanced disease stage, clear cell histology, body mass index (BMI) ≥24kg/m2 at the diagnosis of ovarian cancer, and no recurrence/persistence of ovarian cancer influenced the overall survival. In the subgroup analysis, compared to the after initial ovarian cancer diagnosis group, patients with stage I/II disease, BMI <24kg/m2 at the diagnosis of ovarian cancer, or primary debulking surgery in the during cancer diagnosis group had longer disease-free survival, and overall survival benefit was observed in cases with stage I/II disease, or primary debulking surgery. The diagnostic timing of thromboembolism was not related to disease-free or overall survival of ovarian cancer patients, but associated with that of specific patient subgroups.

Risk of recurrent cancer-associated venous thromboembolism: A Danish nationwide cohort study

BackgroundPredictive factors for recurrent cancer-associated venous thromboembolism have been inconsistent across previous studies. To provide data for improved risk stratification, we described the risk of recurrent venous thromboembolism overall and across age, sex, calendar period, cancer type, Ottawa risk score, cancer stage, and cancer treatment in a nationwide cohort of patients with active cancer. MethodsUsing Danish administrative registries, we identified a cohort of all adult patients with active cancer and a first-time diagnosis of venous thromboembolism during 2003–2018. We accounted for the competing risk of death and calculated absolute risks of recurrent venous thromboembolism at six months. ResultsThe population included 34,072 patients with active cancer and venous thromboembolism. Recurrence risks at six months were higher for patients with genitourinary cancer (6.5%), lung cancer (6.1%), gastrointestinal cancer (5.6%), brain cancer (5.2%), and hematological cancer (5.1%) than for patients with gynecological cancer (4.7%), breast cancer (4.1%), and other cancer types (4.8%). Recurrence risks were similar for men (5.2%) and women (4.9%), with and without chemotherapy (5.1%), across Ottawa risk score group (low: 5.0%; high: 5.1%) and across calendar periods but increased with increasing cancer stage. The overall six-month all-cause mortality risk was 26%, and highest for patients with lung cancer (49%) and lowest among breast cancer patients (4.1%). ConclusionsSix-month recurrence risk after first-time cancer-associated venous thromboembolism was high and varied by cancer type and patient characteristics. Refining risk stratification for recurrence may improve decision-making regarding treatment duration after cancer-associated thromboembolism.

Comparative Efficacy of Oral Apixaban and Subcutaneous Low Molecular Weight Heparins in the Treatment of Cancer-Associated Thromboembolism: A Meta-Analysis.

Cancer patients' risk of developing venous thromboembolism (VTE) is four to seven times higher than the general population. Cancer-associated VTE (CA-VTE), is a leading cause of morbidity and mortality in cancer patients. Low Molecular Weight Heparin (LMWH) has historically been the mainstay treatment ofCA-VTE; however, complications such as bleeding and recurrent VTE make it challenging to manage these patients. Recent randomized controlled trials (RCTs) have proven that direct oral anticoagulants (DOACs) are as efficacious as LMWHs in treating CA-VTE. We conducted a systematic review and meta-analysis to ascertain the efficacy and safety of LMWH and Apixaban for the treatment of CA-VTE.A systematic review was conducted using Medline, Embase, and Scopus, databases for all cohort studies, case-control studies, and RCTs in English comparing cancer patients undergoing treatment with Apixaban or LMWH to treat CA-VTE from inception-May 2023. The Review Manager program, version 5.4.1, was used for statistical analysis and the Mantel-Haenszel fixed-effects models to calculate the risk ratio (RR) and 95% confidence intervals (CIs) and the inverse variance approach to get the weighted mean difference for the continuous outcomes. Q-test for heterogeneity was used to examine statistical heterogeneity and an I2 statistics value >50%was defined as significant heterogeneity. A total of four studies were included, and the total number of patients was 1,632 across all studies. The Apixaban group was associated with a statistically significant increase in minor bleeding (RR 1.57; 95% CI (1.12, 2.21); p=0.009; I2=0%), but not for major and total bleeding. The Apixaban group showed a statistically significant lower risk of recurrent VTE when compared to the LMWH group (RR: 0.61; 95% CI (0.41, 0.92); p=0.02; I2 = 7%), and there was no statistically significant difference in terms of mortality between the two groups (RR: 0.89;95% CI (0.73, 1.09); I2=0). Our findings suggest that Apixaban may be a favorable anticoagulant option for managing cancer-associated thromboembolism, as it demonstrated a lower risk of recurrent VTE. The risk of bleeding with DOAC in gastrointestinal cancers warrants further investigation.

Comparison among three predictive models for cancer-associated thromboembolism in a hispanic population.

In this study we aimed to evaluate and compare the overall performance of the Khorana, PROTECHT, and CONKO scores as predictive scores for the occurrence of venous thromboembolism (VTE) among ambulatory Hispanic patients with solid tumors. We included all outpatients with newly diagnosed solid tumors receiving systemic chemotherapy in Hospital San Juan Dios, San José, Costa Rica, from January to December 2021. For each patient the Khorana, PROTECHT, and CONKO scores were calculated at the beginning of treatment. The sixth-month cumulative incidence of VTE was estimated using the Fine & Gray competing risk model. The receiver operating characteristic (ROC) curve was used to assess the performance of each predictive tool through the analysis of the c-statistic, sensitivity, and specificity. A total of 708 patients were included in the research. After a median follow-up of 8.13 months, the cumulative VTE incidence at six months was 4.45% (95%CI: 3.25-6.91%) for the overall population. At the conventional positivity threshold of 3 points, these scores classified from 17.7 to 32.5% of all patients as high-risk for VTE. Patients belonging to the high-risk category of the Khorana, PROTECHT, and CONKO scores had significantly higher risk of VTE in comparison to low-risk patients (Khorana score: Hazard Ratio (HR): 2.66; 95%CI:1.20-5.89; p = 0.042; PROTECHT score: HR: 3.44; 95%CI:1.63-7.21; p = 0.001; CONKO score HR: 3.68; 95%CI:1.72-7.85; p = 0.001). The c-statistic of the ROC curve was: 0.62 (95%CI: 0.52-0.72), 0.62 (95%CI: 0.52-0.73), and 0.65 (95%CI: 0.56-0.76) for the Khorana, PROTECHT, and CONKO scores, respectively; with similar sensitivity (range: 67-70%) and specificity (range: 52-62%) among them. For Hispanic patients with solid tumors the Khorana, PROTECHT, and CONKO scores accurately categorize their risk of VTE. However, the overall discriminatory performance of these models remains poor (c-statistic from 0.62 to 0.65) for predicting all patients at risk for thromboembolic events.

Current Management of Cancer-Associated Thromboembolism in the Prophylactic and Acute Setting

Current Management of Cancer-Associated Thromboembolism in the Prophylactic and Acute Setting

Comparative Efficacy of Direct Oral Anticoagulants and Low-Molecular-Weight Heparin in Cancer-Associated Thromboembolism: A Systematic Review and Meta-Analysis.

Patients diagnosed with cancer often experience an abnormal occurrence of venous thromboembolism (VTE) and its related complications. In order to evaluate the safety and effectiveness of both treatment approaches, we conducted a comprehensive systematic review and meta-analysis within the realm of cancer-associated thromboembolism. A thorough search was conducted across PubMed, the Cochrane Library, and Embase databases to find studies comparing direct oral anticoagulants (DOACs) with low molecular weight heparins (LMWHs) for the treatment of VTEin patients with malignancy. The analyses utilized the random-effects model. This meta-analysis included 11 studies. The results showed that DOACs were associated with a significantly reduced risk of VTE recurrence (RR: 0.67; 95% CI: 0.55, 0.81, p<0.0001; I2: 0%) and deep vein thrombosis (DVT) (RR: 0.63; 95% CI: 0.46, 0.86, p<0.0001; I2: 0%) compared to LMWHs. However, there was no significant difference in the risk of pulmonary embolism (PE) (RR: 0.76; 95% CI: 0.54, 1.06, p=0.11; I2: 11%) between the two groups. The use of DOACs was also associated with a non-significant increase in the risk of major bleeding events (RR: 1.23; 95% CI: 0.85, 1.78, p: 0.26; I2: 49%), while clinically relevant non-major bleeding (CRNMB) was significantly higher with DOACs (RR: 1.92; 95% CI: 1.11, 3.30, p: 0.02; I2: 81%). Secondary outcomes, such as survival rates and fatal PE, did not show significant differences between the two treatment groups. Our analysis indicates that direct oral anticoagulants exhibit a substantial decrease in the occurrence of VTE recurrence, deep vein thrombosis, and pulmonary embolism when compared to low molecular weight heparin in cancer-associated thromboembolism. However, it should be noted that DOACs carry a higher risk of CRNMB. Based on these findings, DOACs are recommended as a superior therapeutic option for managing cancer-associated thromboembolism compared to LMWH.

Comparison among three predictive models for cancer-associated thromboembolism in a Hispanic population.

e24074 Background: Several predictive scores have been developed to assess the risk of venous thromboembolism (VTE) among cancer patients. Although their use is currently recommended by several guidelines, it is unknown if these scores can accurately predict the risk of VTE in Hispanic patients that are at different risk for thrombosis. Methods: We retrospectively evaluated all outpatients with newly diagnosed solid tumors receiving systemic chemotherapy in Hospital San Juan Dios, San José, Costa Rica, from January to December 2021. For each patient, the Khorana, PROTECHT, and CONKO scores were calculated at the beginning of treatment. The sixth-month cumulative incidence of VTE was estimated using the Fine &amp; Gray competing risk model for the overall population and stratified according to each risk category. A Kaplan-Meier analysis was used to compare the cumulative VTE incidences between high- and low-risk categories of the three predictive scores. The Cox regression analysis was used to calculate the hazard ratio (HR) and its corresponding 95% confidence interval (CI). The receiver operating characteristic (ROC) curve was used to assess the performance of each predictive tool through the analysis of the c-statistic, sensitivity, and specificity. Results: 708 patients were included in the analysis. After a median follow-up of 8.13 months, the cumulative VTE incidence at six months was 4.45% (95%CI: 3.25-6.91%). At the conventional positivity threshold of 3 points, these scores classified from 17.7 to 27.5% of all patients as high-risk for VTE. The 6-month incidence of VTE among high-risk patients ranged from 7.6% for the Khorana score to 9.3% for the CONKO score. Patients belonging to the high-risk category of the Khorana, PROTECHT, and CONKO scores had significantly higher risk of VTE in comparison to low-risk patients (Khorana score: HR: 2.66; 95%CI:1.20-5.89; p = 0.042; PROTECHT score: HR: 3.44; 95%CI:1.63-7.21; p = 0.001; CONKO score HR: 3.68; 95%CI:1.72-7.85; p = 0.001). Table 1 resumes the performance of the studied scores. Table 1. Performance of the Khorana, PROTECHT, and CONKO scores for the prediction of venous thromboembolism. Conclusions: The Khorana, PROTECHT, and CONKO scores accurately predict the risk of VTE in Hispanic patients with solid tumors with similar performance among them. However, their sensitivity and specificity remain poor for identifying all patients at risk for thromboembolic events.[Table: see text]

Efficacy and safety of novel oral anticoagulants for the treatment of cancer-associated venous thromboembolism: protocol for an umbrella review of systematic reviews and meta-analyses

IntroductionNovel oral anticoagulants (NOACs) have been used in antithrombotic therapy in patients with cancer, and their efficacy and safety have been evaluated in several meta-analyses. Although a large body of...

The Saudi Consensus for the Management of Cancer-Associated Thromboembolism: A Modified Delphi-Based Study.

Background  Cancer is a well-known risk factor of preventable thromboembolic disease. This study aims to provide guidance on the prevention and management of cancer-associated thrombosis (CT) that tailors prophylactic and therapeutic options for medical and surgical oncology patients presenting to health care settings in Saudi Arabia. Methods  The present consensus was developed in concordance with the modified Delphi-based approach, which incorporates a face-to-face meeting between two voting rounds to gain experts' feedback on the proposed statements. All experts were either oncologists, hematologists, or hemato-oncologist with an active clinical and research profile in hemato-oncology. Results  The experts highlighted that the comparatively high incidence of inherited thrombophilia among the Saudi population may account for a higher CT burden in the Kingdom than in other parts of the world. However, due to the lack of literature that assesses CT in Saudi Arabia, primary venous thromboembolism prophylaxis should be tailored according to a valid risk assessment of cancer patients and should be implemented in routine practice. For hospitalized medical oncology patients, the experts agreed that prophylaxis with low-molecular-weight heparin (LMWH) should be offered, regardless of the presence of acute illness. For ambulatory medical oncology patients, LMWH or direct oral anticoagulants (DOACs) prophylaxis should be offered for high-risk patients. Concerning surgical patients, they agreed that all oncology patients undergoing surgery should be offered thromboprophylaxis. In terms of secondary prophylaxis, the experts recommended continuing a prophylactic dose of anticoagulant (LMWH or DOAC), for an appropriate period depending on the cancer type and stage. Finally, they also provided a set of statements on management of CT in Saudi Arabia. Conclusion  The present modified Delphi-based study combined the best available evidence and clinical experience with the current health care policies and settings in Saudi Arabia to build a consensus statement on the epidemiology, prevention, and management of CT.

Abstract C028: The lung pro-thrombotic niche drives cancer-associated thromboembolism and metastasis via extracellular vesicle ITGB2

Abstract Thromboembolism (TE) is a common complication in cancer patients and the second leading cause of cancer-related deaths. The incidence of TE varies in different cancer types, with the highest risk in pancreatic ductal adenocarcinoma (PDAC) and in advanced-stage and metastatic cancers. Despite the benefits associated with anti-coagulant therapy for symptomatic TE, the prevention of TE still remains an unmet clinical need due to lack of biomarkers predictive of TE risk and the bleeding risk associated with the routine use of anti-coagulants. Small extracellular vesicles (sEV) mediate cell-to-cell communication. Cancer cells and the tumor microenvironment release large numbers of sEV into the blood circulation and sEVs have displayed a therapeutic and predictive value in systemic diseases. However, the role of sEVs in cancer-associated TE remains to be investigated. Here we show that sEVs from (pre)metastatic lungs of mice with melanoma, breast, lung, and PDAC induce TE in mice and express high levels of integrin beta 2 (ITGB2), while sEVs from tumor cell lines, primary tumors, or other metastasis-bearing organs did not show any pro-thrombotic properties. A specific subtype of interstitial macrophages infiltrating (pre-)metastatic lungs were the main source of ITGB2+ pro-thrombotic sEVs. Blockade of ITGB2 on lung-derived sEVs, or systemically in mice, prevented EV-induced platelet aggregation and TE, and reduced metastasis. Examination of the mechanisms of ITGB2-induced TE showed that EV-associated ITGB2 interacts directly or through fibrin with different binding partners on platelets, and induce their activation and aggregation. Importantly, we found that levels of ITGB2 on sEVs are elevated in the plasma of PDAC patients prior (&amp;lt;30 days) to TE events in comparison to PDAC patients with no history of TE, and thus might serve as prognostic biomarker of TE. Together, our results provide the first evidence of the establishment of a pro-thrombotic lung niche in PDAC as well as other cancer types. Moreover, we identify EV-associated ITGB2 as a new target for the prevention and/or treatment of TE, as well as a potential “liquid biopsy” analyte for the early stratification of patients at high risk of TE. Citation Format: Serena Lucotti, Yusuke Ogitani, Candia M. Kenific, Linda Bojmar, Michele Cioffi, Pernille Lauritzen, Henrik Molina, Soeren Heissel, Henry B. Lengel, Xiaohong Jing, Haiying Zhang, Irina Matei, Eileen M. O'Reilly, William R. Jarnagin, David Jones, James B. Bussel, David Kelsen, Jacqueline F. Bromberg, Diane M. Simeone, David Lyden. The lung pro-thrombotic niche drives cancer-associated thromboembolism and metastasis via extracellular vesicle ITGB2 [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C028.

Abstract 11655: Direct Oral Anticoagulants Compared With Low Molecular Weight Heparin and Vitamin K Antagonists in the Management of Cancer-Associated Thrombosis: A Systematic Review and Network Meta-Analysis

Objective: Low molecular weight heparin (LMWH) has been established for the treatment of cancer-associated thromboembolism (CAT). Recent guidelines suggest Direct Oral Anti-Coagulants (DOACs) may have a role in the management of CAT, however these recommendations were conditional. This study aims to compare DOACs with LMWH and Vitamin K Antagonists (VKAs) in CAT. Methods: We conducted a meta-analysis of studies through a systematic search of four electronic databases (PubMed, Scopus, Web of Science, and Cochrane) published before January 25, 2022. Our criteria included studies in patients with all cancer types who received DOACs, VKAs, or LMWH for prevention or treatment of CAT. We analyzed outcomes including recurrent venous thromboembolism, major bleeding, clinically relevant non-major bleeding (CRNMB), and all-cause mortality. The quality assessment of the included RCTs was conducted through Cochrane Tool, while the quality of the included cohort studies was assessed by the NIH tool. The network meta-analysis was performed using the netmeta package in R software. Results: A total of 55 studies were included; 18 RCTs, and 37 cohort studies. DOACs (RR= 0.72, 95% CI [0.63; 0.83]) and LMWH (RR= 0.78, 95% CI [0.64; 0.94]) had a significantly lower risk of major bleeding than VKAs. There was also a significantly decreased risk of clinically relevant non-major bleeding (CRNMB) with LMWH than DOACs (RR= 0.63, 95% CI [0.55; 0.73]) and DOACs compared to VKA (RR= 0.83, 95% CI [0.72; 0.95]). With regards to recurrent venous thromboembolism risk (VTE), DOACs showed a significantly lower risk compared with either LMWH (RR=0.70, 95% CI [0.59; 0.83]) or VKA (RR=0.66, 95% CI [0.54; 0.80]). Conclusion: We conclude that DOACs are more effective in the management of CAT when compared to LMWH and VKA. DOACs and LMWH have significantly lower risk of major bleeding when compared to VKA. More research is needed to determine the best anticoagulation strategy for distinct types of cancers.

Tissue factor in cancer-associated thromboembolism: possible mechanisms and clinical applications.

Venous and arterial thromboses, called as cancer-associated thromboembolism (CAT), are common complications in cancer patients that are associated with high mortality. The cell-surface glycoprotein tissue factor (TF) initiates the extrinsic blood coagulation cascade. TF is overexpressed in cancer cells and is a component of extracellular vesicles (EVs). Shedding of TF+EVs from cancer cells followed by association with coagulation factor VII (fVII) can trigger the blood coagulation cascade, followed by cancer-associated venous thromboembolism in some cancer types. Secretion of TF is controlled by multiple mechanisms of TF+EV biogenesis. The procoagulant function of TF is regulated via its conformational change. Thus, multiple steps participate in the elevation of plasma procoagulant activity. Whether cancer cell-derived TF is maximally active in the blood is unclear. Numerous mechanisms other than TF+EVs have been proposed as possible causes of CAT. In this review, we focused on a wide variety of regulatory and shedding mechanisms for TF, including the effect of SARS-CoV-2, to provide a broad overview for its role in CAT. Furthermore, we present the current technical issues in studying the relationship between CAT and TF.

Thromboembolism and Immune Checkpoint Blockade in Cancer Patients: An Old Foe for New Research.

Patients with cancer are at an increased risk of venous (VTE) and arterial thromboembolism (ATE), and thromboembolic events (TEs) represent the second-leading cause of death in cancer patients. The risk of cancer-associated thromboembolism is multifactorial. In addition to patient risk factors, anticancer treatments have been found to increase the risk of both VTE and ATE. Immune checkpoint blockade (ICB) has become a mainstay of treatment in various types of cancers. Their use is associated with the occurrence of a new spectrum of side effects called immune-related adverse events. Meta-analyses-including data from prospective and retrospective studies-and case reports both reported VTE and ATE as adverse events associated with ICB, with a cumulative incidence equaling around 3% and 1%, respectively. The exact mechanism underlying a TE after ICB use is currently unclear, as well as its associated risk factors. Considering their potential life-threatening impact, it is important for clinicians to be aware of the potential thrombotic complications, to educate patients and recognize early signs and symptoms of VTE and ATE, in order to allow prompt treatment (if needed) and avoid complications.

Management of Cancer-Associated Thrombosis in France: A National Survey among Vascular Disease and Supportive Care Specialists.

Low molecular weight heparins (LMWHs) are recommended by international guidelines for at least 6 months in patients with cancer-associated thromboembolism (CAT). Direct oral anticoagulants (DOACs) have been proposed as an alternative to LMWH. In clinical practice, the specialists in charge of CAT have to decide which anticoagulant to prescribe. An electronic survey tool, including vignettes and questions, was sent to members of the French Society of Vascular Medicine, the French-speaking association for supportive care in oncology and the Investigation Network On Venous Thrombo-Embolism. Among the 376 respondents, LMWHs were reported as the first choice by most specialists. The prescription of DOACs within the first 3 weeks of CAT diagnosis was highly dependent on the cancer site: 5.9%, 18.6% and 24.5% in patients with locally advanced colorectal, lung and breast cancer, respectively. The determinants were mostly related to cancer (site and stage or evolution) and to anticancer treatments. For 61% of physicians, some anticancer treatments were contraindications to DOACs. However, almost 90% of physicians considered switching to DOAC after a median 3-month period of LMWHs. In daily practice, LMWHs and DOACs are now considered by specialists of CAT; the decision is mostly driven by the site of cancer. The role of anticancer treatments in the decision remains to be investigated.

IMPROVE bleeding score predicts major bleeding in advanced gastrointestinal cancer patients with venous thromboembolism.

The incidence of venous thromboembolism has been reported as 20% in cancer patients. Anticoagulation therapy is the standard treatment for venous thromboembolism. On the other hand, bleeding should be carefully managed, because advanced cancer, particularly gastrointestinal cancer, carries a high risk of bleeding. However, the optimal management for cancer-associated thromboembolism remains to be clarified. We retrospectively examined patients with advanced gastrointestinal cancer, including gastric cancer and colorectal cancer, who were treated with chemotherapy between 2014 and 2018 for the incidence and characteristics of venous thromboembolism and bleeding. In total, 194 patients (120 men, 74 women) were enrolled in this study. The underlying pathology was gastric cancer in 74 cases and colorectal cancer in 120 cases. Of the 194 patients, 40 patients (20.6%) were diagnosed with venous thromboembolism and 10 patients (5.2%) were diagnosed with concomitant pulmonary thromboembolism. Conversely, bleeding was observed in 29 patients (15%). The location of bleeding was the primary tumor in 17 cases, metastatic tumor in 9 and hemorrhagic gastric ulcer in 3. Within the venous thromboembolism group (n=40), bleeding was observed in 10 patients (25%). Multivariate analysis showed that International Medical Prevention Registry on Venous Thromboembolism (IMPROVE) bleeding score ≥7 correlated significantly with major bleeding (P=0.01). In patients with a low risk of bleeding, major bleeding was observed in only three patients. IMPROVE bleeding score may predict the risk for bleeding in gastrointestinal cancer patients with venous thromboembolism. Selecting patients with a low risk of bleeding using with IMPROVE bleeding score is expected to contribute to the safer management of anticoagulation therapy for cancer-associated thromboembolism.

Abstract 3138: The lung pro-thrombotic niche drives cancer-associated thromboembolism via exosomal ITGB2

Abstract Thromboembolism (TE) is a common complication in cancer patients and the second leading cause of cancer-related deaths. The incidence of TE varies in different cancer types, with the highest risk in lung cancer and pancreatic ductal adenocarcinoma (PDAC), and in advanced-stage and metastatic cancers. Despite the benefits associated with thromboprophylaxis for symptomatic TE, the prevention of TE still remains an unmet clinical need due to lack of biomarkers predictive of TE risk and the bleeding risk associated with the routine use of anti-coagulants. Exosomes are small circulating extracellular vesicles that mediate cell-to-cell communication. Cancer cells and the tumor microenvironment release large numbers of exosomes into the blood circulation and have displayed a therapeutic and predictive value in systemic diseases. Integrins expressed on the surface of exosomes drive their selective organotropism and prepare distant sites for metastatic seeding by establishing favorable pre-metastatic niches. Here we show that exosomes from metastasis-bearing lungs or pre-metastatic lungs of mice with melanoma, breast, lung and pancreatic cancer induce TE in mice and express high levels of integrin beta 2 (ITGB2). Instead, exosomes from tumor cell lines, primary tumors or other metastasis-bearing organs did not show any pro-thrombotic properties. Myeloid cells including monocytes/macrophages and neutrophils infiltrating pre- and post-metastatic lungs were the main source of ITGB2+ pro-thrombotic exosomes. Blockade of ITGB2 on lung-derived exosomes, or systemically in mice, prevented exosome-induced platelet aggregation and TE, and reduced metastasis. Examination of the mechanisms of ITGB2-induced TE showed that exosomal ITGB2 interact directly or through fibrin with different binding partners on platelets, and induce their activation and aggregation. Importantly, we found that exosomal ITGB2 levels are elevated in the plasma of PDAC patients prior to TE events in comparison to PDAC patients with no history of TE, and thus might serve as prognostic biomarker of TE. Together, our results provide the first evidence of the establishment of a pro-thrombotic lung niche in different cancer types. Moreover, we identify exosomal ITGB2 as a new target for the prevention and/or treatment of TE, as well as a potential “liquid biopsy” analyte for the early stratification of patients at high risk of TE. Citation Format: Serena Lucotti, Yusuke Ogitani, Candia M. Kenific, Linda Bojmar, Michele Cioffi, Pernille Lauritzen, Henrik Molina, Soren Heissel, Harry B. Lengel, Xiaohong Jing, Haiying Zhang, Irina Matei, Eileen M. O'Reilly, William R. Jarnagin, David R. Jones, James B. Bussel, David Kelsen, Jacqueline F. Bromberg, Diane M. Simeone, David Lyden. The lung pro-thrombotic niche drives cancer-associated thromboembolism via exosomal ITGB2 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3138.

Inpatient primary prophylaxis of cancer-associated thromboembolism (CAT)

Cancer-associated thrombosis (CAT) increases morbidity and mortality in oncology patients. The risk of CAT is increased with hospitalization for acute medical illness. The goal of this review will be to examine the available evidence for (1) risk assessment and (2) primary thromboprophylaxis, (3) international published guideline recommendations, and (4) future directions to manage oncology patients admitted for an acute medical illness. A review was performed for each subject to gather information on the available evidence and recommendations available for oncology patients hospitalized for an acute medical illness. Risk assessments for thrombosis are primarily developed and validated in the general population. There is not a risk assessment that has specifically been developed and validated in oncology patients hospitalized for an acute medical illness. Most evidence for thromboprophylaxis of oncology patients is from sub-group analysis of larger randomized-controlled trials in the general population. Evidence is conflicting and suggests an individualized approach evaluating the risk-benefit of thromboprophylaxis. The strength of recommendations of international guidelines is limited because of the available evidence. Guidelines usually recommend utilizing and/or offering thromboprophylaxis to oncology patients hospitalized for an acute medical illness barring contraindications. Future evidence needs to improve risk assessments and knowledge of the appropriate agent, dose, and duration of thromboprophylaxis if indicated. Evidence for risk assessments and primary prophylaxis for oncology patients hospitalized for acute medical illness appears limited, with many research opportunities available to improve understanding on management of this patient population.