多癌种恶性肿瘤相关静脉血栓的多组学标志物、风险模型与重点蛋白促凝机制

Cancer patients have an increased risk of venous thromboembolism (VTE). In this review, we summarize common and cancer type–specific pathways of VTE in cancer patients. Increased levels of leukocytes, platelets, and tissue factor–positive (TF+) microvesicles (MVs) are all potential factors that alone or in combination increase cancer-associated thrombosis. Patients with lung or colorectal cancer often exhibit leukocytosis. Neutrophils could increase VTE in cancer patients by releasing neutrophil extracellular traps whereas monocytes may express TF. Thrombocytosis is often observed in gastrointestinal, lung, breast, and ovarian cancer and this could decrease the threshold required for VTE. Soluble P-selectin has been identified as a biomarker of cancer-associated thrombosis in a general cancer population and may reflect activation of the endothelium. P-selectin expression by the endothelium may enhance VTE by increasing the recruitment of leukocytes. Studies in patients with pancreatic or brain cancer suggest that elevated levels of PAI-1 may contribute to VTE. Although elevated levels of TF+ MVs have been observed in patients with different types of cancer, an association between TF+ MVs and VTE has been observed only in pancreatic cancer. Podoplanin expression is associated with VTE in patients with brain cancer and may activate platelets. Future studies should measure multiple biomarkers in each cancer type to determine whether combinations of biomarkers can be used as predictors of VTE. A better understanding of the pathways that increase VTE in cancer patients may lead to the development of new therapies to reduce the morbidity and mortality associated with thrombosis.

Cancer-associated thrombosis is a leading cause of non-cancer death in cancer patients and is comprised of both arterial and venous thromboembolism. There are multiple risk factors for developing VTE, including cancer type, stage, treatment, and other medical comorbidities, which suggests that the etiology of thrombosis is multifactorial. While cancer-associated thrombosis can be treated with anticoagulation, benefits of therapy must be balanced with the increased bleeding risks seen in patients with cancer. Although risk models exist for primary and recurrent VTE, additional predictors are needed to improve model performance and discrimination of high-risk patients. This review will outline the diverse mechanisms driving thrombosis in cancer patients, as well as provide an overview of biomarkers studied in thrombosis risk and important considerations when selecting candidate biomarkers.

… in cancer patient outcomes. In this review we will discuss risk factors and biomarkers for development of VTE in cancer patients and a risk stratification model aimed at identifying cancer …

Abstract Emerging data have enhanced our understanding of cancer-associated thrombosis, a major cause of morbidity and mortality in patients with cancer. This update will focus on recent findings, including the phenomenon of incidental venous thromboembolism (VTE), novel approaches to risk assessment, and the results of randomized clinical trials focusing on prophylaxis of cancer outpatients. Incidental VTE is an important contributor to rates of cancer-associated VTE and, in terms of outcomes, appears to be as consequential for patients as symptomatic VTE. Multiple biomarkers have been studied, with the highest level of evidence for prechemotherapy elevated platelet counts, elevated leukocyte counts, and low hemoglobin. Other candidate biomarkers, including D-dimer and tissue factor, are currently being evaluated. A recently validated risk score for chemotherapy-associated VTE has now been evaluated in more than 10 000 cancer patients in a variety of clinical settings and trials and is ready for clinical use (Level 1 clinical decision rule). Several randomized clinical trials in solid-tumor patients with low-molecular-weight heparins and semuloparin, an ultra-low-molecular-weight heparin, demonstrate clearly that outpatient thromboprophylaxis is feasible, safe, and effective. Selecting the appropriate patients for prophylaxis, however, continues to be a matter of controversy.

… This review will focus on the risk factors for VTE in cancer patients, candidate biomarkers, and a recently validated risk model for identifying patients at high risk in ambulatory setting. …

Simple Summary Cancer-associated thrombosis (CAT) is a severe cause of mortality and morbidity in cancer patients, while active cancer is present in 20% of all patients with venous thromboembolism (VTE). CAT presents several peculiarities that distinguish this entity from other clinical settings associated with VTE. Management of thromboembolic events in CAT is extremely challenging because of the multifactorial pathophysiology of this clinical setting. The objective of this review is to enlighten the complicated pathophysiology of CAT, discuss the available biomarkers for early identification of high-risk patients, and summarize the current guidelines regarding the treatment and management of thrombotic events in cancer patients. Abstract Dysregulated hemostasis in cancer patients is associated with various clinical conditions, from thromboembolic complications to disseminated intravascular coagulation. Despite the well-established association between cancer and thromboembolic complications, the mechanisms involved are not completely elucidated. There are several predisposing factors in cancer for increased thrombus generation, such as immobilization and chemotherapy. The term cancer-associated thrombosis (CAT) has been introduced to describe the close bidirectional relationship between cancer and thromboembolic events. Conventional coagulation tests (PT/aPTT) are more accurate in detecting a hypocoagulable rather than a hypercoagulable state; thus, their contribution to CAT management is limited. Traditionally, D-dimer levels have been the most common laboratory study for the evaluation of thrombotic risk. However, D-dimer levels only display a snapshot of the coagulation cascade, and they cannot provide a dynamic evaluation of evolving clot formation. Non-conventional assays, such as viscoelastic methods and microparticle formation are promising tools for the identification of patients at risk for developing CAT. Recent guidelines from the American Society of Clinical Oncology counsel against the estimation of thrombotic risk through a single test and recommend the use of scoring systems that take into account several risk factors. The present review outlines the current insights into the pathophysiological mechanisms of CAT and provides a comprehensive review of the latest advances in the laboratory assessment of CAT and the recent guidelines for the management of patients at risk for developing thromboembolic complications.

… (Table 1) in cancerassociated thrombosis is well known. Differently… of VTE events of several circulating thrombotic biomarkers. … : A new link to cancerassociated thrombosis and potential …

Cancer patients are at increased risk of deep vein thrombosis and pulmonary embolism. The incidence among different groups of cancer patients varies considerably depending on clinical factors, the most important being tumor entity and stage. Biomarkers have been specifically investigated for their capacity of predicting venous thromboembolism (VTE) during the course of disease. Parameters of blood count analysis (elevated leukocyte and platelet count and decreased hemoglobin) have turned out to be useful in risk prediction. Associations between elevated levels and future VTE have been found for d-dimer, prothrombin fragment 1+2, and soluble P-selectin and also for clotting factor VIII and the thrombin generation potential. The results for tissue factor–bearing microparticles are heterogeneous: an association with occurrence of VTE in pancreatic cancer might be present, whereas in other cancer entities, such as glioblastoma, colorectal, or gastric carcinoma, this could not be confirmed. Risk assessment models were developed that include clinical and laboratory markers. In the high-risk categories, patient groups with up to a >20% VTE rate within 6 months can be identified. A further improvement in risk stratification would allow better identification of patients for primary VTE prevention using indirect or novel direct anticoagulants.

… -associated thrombosis. Table 5.1 lists the common biomarkers for cancer-associated thrombosis … Many of the above-mentioned biomarkers are also known to increase with other …

… accurate, numerous groups have reported their correlation as biomarkers of ongoing coagulation. In some cases, tissue factor associated with microparticles has been implicated in the …

Cancer-associated thrombosis (CAT) is a leading cause of morbidity and mortality among cancer patients. While venous thromboembolic events have been extensively studied due to their higher incidence, arterial thrombosis in cancer patients—referred to as cancer-associated arterial thromboembolism (CA-ATE)—is less well understood but may pose a greater danger. The pathophysiology of CA-ATE involves complex interactions between the tumor microenvironment, cancer cells, patient-related factors, and cancer therapies. Some chemotherapeutic agents, particularly platinum-based compounds (cisplatin, oxaliplatin), gemcitabine, taxanes, and targeted therapies such as tyrosine kinase inhibitors (TKIs), have been associated with an increased risk of arterial thrombosis. In certain patient populations, hormonal therapy and selective estrogen receptor modulators may also contribute to this risk. Additionally, factors such as patient age, cancer type, and stage contribute to an increased risk of arterial thrombosis in this population. Key mechanisms driving CA-ATE include endothelial injury, hypercoagulability, and platelet activation. Certain malignancies, notably lung and pancreatic cancers, are associated with a higher incidence of arterial thrombotic events. The aim of this review is to enhance understanding of the underlying mechanisms of cancer-related arterial thromboembolism and to highlight the various therapeutic, cancer-related, and patient-related factors that contribute to the occurrence of cancer-associated arterial thrombotic events.

… biomarker for cancer-associated thrombosis. In a prospective cohort of 219 ambulatory patients initiating cancer … tumour-platelet interactions, was associated with an increased risk of …

Background & Objectives: Venous thromboembolism (VTE) is a major cardiovascular complication in cancer patients and leading cause of morbidity and mortality. The aim of the study was to evaluate the incidence, timing, clinical predictors, and management of VTE in patients with breast cancer (BC), undergoing oncological therapy, and to propose a risk-adapted strategy for thrombosis monitoring and prevention. Methods: In this retrospective single-center study, 116 women with histologically confirmed BC (stages I–IV) treated between 2021 and 2024 were included. Patients were divided according to the occurrence of objectively confirmed VTE. Clinical characteristics, comorbidities, laboratory parameters, cancer-related factors, and treatment modalities were analyzed. Univariate and multivariate logistic regression analyses were performed to identify independent predictors of VTE. Results: VTE occurred in 25 patients (21.6%), predominantly within the first 12 months after cancer diagnosis. Patients who developed VTE were significantly older and more frequently had hypertension, dyslipidemia, hyperglycemia, anemia, and leukocytosis. Multivariate analysis identified age≥55 years, poor performance status (ECOG ≥3), and elevated glucose level as independent predictors of VTE. Deep vein thrombosis of the lower and upper extremities was the most common manifestation (52%), while pulmonary embolism was present in 24% of cases, either alone or in combination (20%). Direct oral anticoagulants were the most frequently used long-term anticoagulant therapy. Conclusions: VTE is a clinically relevant and relatively frequent complication in patients with BC, particularly during the early period of anticancer treatment. Patient-related and metabolic factors play a key role in thrombosis risk, underscoring the need for individualized, risk-adapted approaches to VTE prevention and monitoring in these populations.

Venous and arterial thromboembolism are prevalent, highly burdensome, and associated with risk of worse outcomes for patients with cancer. Risk for venous thromboembolism (VTE) varies widely across specific cancer subpopulations. The ability to predict risk of cancer-associated VTE is critical because an optimal thromboprophylaxis strategy is best achieved by targeting high-risk patients with cancer and avoiding prophylaxis in patients with cancer at low risk for VTE. A validated risk tool for solid tumors has been available for a decade. Newer tools have focused on specific populations, such as patients with multiple myeloma. Emerging studies continue to optimize risk prediction approaches in patients with cancer. Recent randomized trials have specifically addressed risk-adapted thromboprophylaxis using direct oral anticoagulants, and revised guidelines have included these new data to formulate recommendations for outpatient thromboprophylaxis. Implementation science approaches to enhance use of outpatient prophylaxis in the context of these guideline changes are under way. However, major knowledge gaps remain, including a lack of data for inpatient thromboprophylaxis in the cancer setting and a lack of formal tools for identifying risk of bleeding. This review describes optimal approaches to risk prediction and patient selection for primary pharmacologic thromboprophylaxis of cancer-associated VTE, addresses barriers to implementing these practices, and highlights strategies to overcome them. IMPLICATIONS FOR PRACTICE: Risk for venous thromboembolism (VTE) varies widely among patients with cancer. Individual risk can be determined using validated approaches. Inpatient and postsurgical thromboprophylaxis is more widely accepted. However, most patients with cancer develop VTE in the outpatient setting. Recent randomized trials have demonstrated benefit to risk-adapted outpatient thromboprophylaxis. High-risk patients may therefore be considered for outpatient thromboprophylaxis as recommended by recently updated guidelines. System-wide implementation approaches are necessary to improve compliance with prophylaxis.

Venous thromboembolism (VTE) is a leading cause of cardiovascular mortality. The diagnosis of acute VTE is based on complex imaging exams due to the lack of biomarkers. Recent multi-omics based research has contributed to the development of novel biomarkers in cardiovascular diseases. Our aim was to determine whether patients with acute VTE have differences in the metabolomic profile compared to non-acute VTE. This observational trial included 62 patients with clinical suspicion of acute deep vein thrombosis or pulmonary embolism, admitted to the emergency room. There were 50 patients diagnosed with acute VTE and 12 with non-acute VTE conditions and no significant differences were found between the two groups for clinical and demographic characteristics. Metabolomics assays identified and quantified a final number of 91 metabolites in plasma and 55 metabolites in red blood cells (RBCs). Plasma from acute VTE patients expressed tendency to a specific metabolomic signature, with univariate analyses revealing 23 significantly different molecules between acute VTE patients and controls (p < 0.05). The most relevant metabolic pathway with the strongest impact on the acute VTE phenotype was d-glutamine and d-glutamate (p = 0.001, false discovery rate = 0.06). RBCs revealed a specific metabolomic signature in patients with a confirmed diagnosis of DVT or PE that distinguished them from other acutely diseased patients, represented by 20 significantly higher metabolites and four lower metabolites. Three of those metabolites revealed high performant ROC curves, including adenosine 3′,5′-diphosphate (AUC 0.983), glutathione (AUC 0.923), and adenine (AUC 0.91). Overall, the metabolic pathway most impacting to the differences observed in the RBCs was the purine metabolism (p = 0.000354, false discovery rate = 0.68). Our findings show that metabolite differences exist between acute VTE and nonacute VTE patients admitted to the ER in the early phases. Three potential biomarkers obtained from RBCs showed high performance for acute VTE diagnosis. Further studies should investigate accessible laboratory methods for the future daily practice usefulness of these metabolites for the early diagnosis of acute VTE in the ER.

… , knowledge of other diagnostic and prognostic biomarkers of VTE/AIS in children remains … AIS (including VIPS) along with new multi-omicscompatible sample processing methods offer …

OBJECTIVE The study was designed with the aim of excavating diagnostic biomarkers of venous thromboembolism (VTE). METHODS The GSE19151 and GSE48000 datasets were subjected into this study. The pyroptosis-related genes (PRGs) were sourced from literature1. Differential expression analysis and WGCNA were applied to identify differential genes related with Pyroptosis (DE-PRGs) in VTE. The possible functions of DE-PRGs were defined by means of enrichment analysis. The biomarkers related with pyroptosis in VTE were determined by plotting receiver operating characteristic (ROC) curve. The gene set enrichment analysis (GSEA) was employed to analyze the correlation between biomarkers and pathways. Finally, the quantificational Reverse Transcription-Polymerase Chain Reaction (qRT-PCR) was proceeded to verify the expression level of the biomarkers in VTE. RESULTS A number of 52 DE-PRGs were identified by feat of differential expression analysis and WGCNA. A number of five biomarkers (RPL31, RPL34, RPL9, RPS27L and HINT1) were further screened by ROC curves. GSEA pointed to the linkage of five biomarkers to the ribosome proteins and oxidative phosphorylation signaling transduction, which may cause cell pyrodeath and trigger VTE through mitochondrial pathways. qRT-PCR manifested the expression levels of RPL31, RPL9 and HINT1 were all observably higher in VTE samples than in normal samples. CONCLUSION A number of five biomarkers, RPL31, RPL34, RPL9, RPS27L and HINT1, were identified as pyroptosis-related biomarkers in VTE, which provided a basis for understanding VTE pathogenesis and new insights into VTE diagnosis and treatment.

Graphical Abstract

Introduction: Venous thromboembolism (VTE), encompassing deep vein thrombosis (DVT) and pulmonary embolism (PE), is a major cardiovascular disorder and a leading cause of vascular mortality. MicroRNAs (miRNAs) are small endogenous noncoding RNAs that regulate gene expression post-transcriptionally by binding to the target messenger RNAs (mRNAs), inducing mRNA degradation or translational repression. miRNA dysregulation likely contributes to VTE pathogenesis. This review comprehensively summarizes current evidence on miRNAs in VTE, offering a structured overview of the existing literature. Materials and Methods: Eligibility criteria were defined using the Population, Intervention/Exposure, Comparator, Outcomes, and Study design (PICOS) framework. A comprehensive literature search in PubMed and EMBASE was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Given methodological heterogeneity, a narrative synthesis was undertaken. Results: Among the 156 studies included in this review, 99 investigated miRNAs in DVT, 25 examined the role of miRNAs in PE, and 32 evaluated miRNA involvement in VTE. These miRNAs were categorized as prothrombotic, antithrombotic, or unclassified based on their reported functional roles. Conclusions: This systematic review highlights the impact of miRNAs in the pathophysiology of VTE and provides a resource for future mechanistic and translational research. The findings emphasize the need for standardized, large-scale studies focusing on human-specific models to validate miRNAs as diagnostic, prognostic biomarkers, and as therapeutic targets in VTE.

Pulmonary embolism (PE) is a common and potentially fatal thromboembolic disease contributing to a major global public health burden. Its pathogenesis involves multiple hemodynamic, inflammatory, metabolic, and genetic factors. The multifactorial nature of PE makes it difficult to infer the direct effects of risk factors using conventional statistical approaches because of potential confounding and reverse causality. Mendelian randomization (MR) uses genetic variants as instrumental variables to strengthen causal inference. This narrative review synthesizes the available MR literature concerning potential causative factors of PE, with particular emphasis on genetic and biological pathways. MR evidence suggests that matrix metalloproteinases (MMP)-19 may be associated with increased PE susceptibility, whereas MMP-12 may be associated with decreased susceptibility. Impaired kidney function showed a positive association with PE risk, and reduced HLA-DR+ NK cell traits were linked to PE pathogenesis. Among gut microbiota, Clostridium innocuum was associated with increased PE risk, whereas Butyricicoccus and Actinobacteria showed protective associations. No consistent causal associations were identified for type 2 diabetes, atrial fibrillation, or epigenetic age acceleration. Larger multiethnic studies integrating multi-omics data are needed to clarify mechanisms underlying PE pathogenesis.

… balance between thrombosis and bleeding.(7) Ischemia caused by vascular thrombosis can lead … the changes of metabolites and potential biomarkers in BSS of different diseases from …

  Medical research has been revolutionized after the publication of the full human genome. This was the major landmark that paved the way for understanding the biological functions of different macro and micro molecules. With the advent of different high-throughput technologies, biomedical research was further revolutionized. These technologies constitute genomics, transcriptomics, proteomics, metabolomics, etc. Collectively, these high-throughputs are referred to as multi-omics technologies. In the biomedical field, these omics technologies act as efficient and effective tools for disease diagnosis, management, monitoring, treatment and discovery of certain novel disease biomarkers. Genotyping arrays and other transcriptomic studies have helped us to elucidate the gene expression patterns in different biological states, i.e. healthy and diseased states. Further omics technologies such as proteomics and metabolomics have an important role in predicting the role of different biological molecules in an organism. It is because of these high throughput omics technologies that we have been able to fully understand the role of different genes, proteins, metabolites and biological pathways in a diseased condition. To understand a complex biological process, it is important to apply an integrative approach that analyses the multi-omics data in order to highlight the possible interrelationships of the involved biomolecules and their functions. Furthermore, these omics technologies offer an important opportunity to understand the information that underlies disease. In the current review, we will discuss the importance of omics technologies as promising tools to understand the role of different biomolecules in diseases such as cancer, cardiovascular diseases, neurodegenerative diseases and diabetes. SUMMARY POINTS

… The current development of risk assessment models to predict thrombosis in cancer is … Many factors contribute to the thrombotic risk in cancer patients, including classical thrombotic risk …

BACKGROUND While the number of models for predicting the risk of cancer-associated thrombosis has been rising, there is still a lack of comprehensive assessment for machine learning prediction models. OBJECTIVE To critically appraise and quantify the performance studies using machine learning to predict cancer-associated thrombosis. METHODS We conducted searches on PubMed, Embase, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, and other related databases for the related publications (from inception to December 1, 2023). The Prediction Model Risk of Bias Assessment Tool checklist was employed to evaluate the risk of bias and applicability. The Grading of Recommendations Assessment, Development and Evaluation system was used to evaluate the quality of evidence in systematic reviews. Meta-analyses were conducted using R (version 4.3.2). RESULTS A total of thirty-two studies were included. Mostly included literature exhibits a high risk of bias, and the applicability of the prediction models is deemed acceptable. The twenty-one included studies in the meta-analysis demonstrated the high predictive capacity of the machine learning models for cancer-associated thrombosis. CONCLUSION Most of the prediction models included in the study showed good applicability and excellent prediction performance, but there was a high risk of bias.

The COMPASS‐CAT study was undertaken in outpatients with breast, colon, lung, or ovarian cancer. The aim of the study was to identify the most relevat risk factors for symptomatic thromboembolism and to develop a risk assessment model applicable to patients after the initiation of anticancer treatment.

Context .—Cancer is characterized by the development of a prothrombotic state. Approximately 15% to 20% and 1.5% to 3.1% of cancer patients develop venous and arterial thrombosis, respectively, whereas 18% to 20% of idiopathic venous events are caused by an occult neoplasia. The highest risk is observed in hematologic, gastrointestinal, and lung malignancies, as well as in patients with active disease, especially in the first 3 months after cancer diagnosis. Hospitalization, surgical interventions, and implanted venous devices increase the thrombotic risk. Patients with metastatic disease, febrile neutropenia, infections, and severe comorbidities experience more frequently a thrombotic event. A contemporary prechemotherapy predictive model incorporates both clinical and biologic parameters, such as the primary cancer site, platelet count, white blood cell count, hemoglobin, use of erythropoietic agents, and body mass index. Several studies aim to clarify the prognostic value of tissue factor, P-selectin, thrombin generation, microparticles, and D-dimers. Objectives .—To summarize current views on epidemiology, risk factors, and predictive variables, discussing the future perspectives and existing limitations in clinical practice. Data Sources .—Review of published literature, including review papers, epidemiologic studies, and clinical trials, in online medical databases. Conclusions .—The thrombogenic properties of tumor cells affect the prognosis and quality of life for the cancer population. Despite the improved awareness and prompt use of thromboprophylaxis, recent studies reported increased rates of thrombotic events, whereas the annual risks for thrombosis recurrence and bleeding are 21% and 12%, respectively. The clinical use of risk factors and prognostic parameters could allow for patient risk stratification and individualization of anticoagulant treatment.

Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. Outpatients with cancer should be periodically assessed for VTE risk, for which the Khorana score is commonly recommended. However, it has been questioned whether this tool is sufficiently accurate at identifying patients who should receive thromboprophylaxis. The present work proposes a new index, TiC-Onco risk score to be calculated at the time of diagnosis of cancer, that examines patients’ clinical and genetic risk factors for thrombosis. We included 391 outpatients with a recent diagnosis of cancer and candidates for systemic outpatient chemotherapy. All were treated according to standard guidelines. The study population was monitored for 6 months, and VTEs were recorded. The Khorana and the TiC-Onco scores were calculated for each patient and their VTE predictive accuracy VTEs was compared. We recorded 71 VTEs. The TiC-Onco risk score was significantly better at predicting VTE than the Khorana score (AUC 0.73 vs. 0.58, sensitivity 49 vs. 22%, specificity 81 vs. 82%, PPV 37 vs. 22%, and NPV 88 vs. 82%). TiC-Onco risk score performed significantly better than Khorana score at identifying cancer patients at high risk of VTE who would benefit from personalised thromboprophylaxis.

… data on clinical risk factors, predictive biomarkers and risk assessment tools with an emphasis on identifying best practice approaches to assessing risk of VTE in the cancer patient. …

A B S T R A C T Important progress has been made in the development of risk assessment models (RAM) for the identification of outpatients on anticancer treatment at risk of venous thromboembolism (VTE). Since the breakthrough publication of the original Khorana risk score (KRS) more than 10 years ago, a new generation of KRS-based scores have been developed, including the Vienna Cancer and Thrombosis Study, PROTECHT, CONKO, ONCOTEV, TicOnco and the CATS/MICA score. Among these the CATS/MICA score showed that a simplified score composed of only two calibrated predictors, the type of cancer and the D-dimer levels, offers a user-friendly tool for the evaluation of cancer-associated thrombosis (CAT) risk. The COMPASS-CAT score is the first that introduced a more synthetic approach of risk evaluation by combining cancer-related predictors with patient comorbidity in a score which is designed for the types of cancer frequently seen in the community (i.e. breast, lung colon or ovarian cancers) and has been externally validated in independent studies. The Throly score is registered as part of the same group as it has a similar structure to the COMPASS-CAT score and is applicable in patients with lymphoma. The incorporation of specific biomarkers of hypercoagulability to the RAM for CAT offers the possibility to perform a precision medicine approach in the prevention of CAT. The improvement of RAM for CAT with artificial intelligence methodologies and deep learning techniques is the challenge in the near future.

… Clinical prediction rules are appealing because they offer several potential benefits for … prediction rule to stratify VTE recurrence risk in patients with cancer-associated thrombosis …

PURPOSE Venous thromboembolism (VTE), especially pulmonary embolism (PE) and lower extremity deep vein thrombosis (LE-DVT), is a serious and potentially preventable complication for patients with cancer undergoing systemic therapy. METHODS Using retrospective data from patients diagnosed with incident cancer from 2011-2020, we derived a parsimonious risk assessment model (RAM) using least absolute shrinkage and selection operator regression from the Harris Health System (HHS, n = 9,769) and externally validated it using the Veterans Affairs (VA) health care system (n = 79,517). Bootstrapped c statistics and calibration curves were used to assess external model discrimination and fit. Dichotomized risk strata using integer scores were created and compared against the Khorana score (KS). RESULTS Incident VTE and PE/LE-DVT at 6 months occurred in 590 (6.2%) and 437 (4.6%) patients in HHS and 4,027 (5.1%) and 3,331 (4.2%) patients in the VA health care system. Assessed at the time of systemic therapy initiation, the new RAM included components of the KS with the modified cancer subtype, cancer staging, systemic therapy class, history of VTE, history of paralysis/immobility, recent hospitalization, and Asian/Pacific Islander race. The c statistic was 0.71 in HHS and 0.68 in the VA health care system (compared with 0.65 and 0.60, respectively, for KS). Furthermore, the new RAM appropriately reclassified 28% of patients and increased the proportion of VTEs in the high-risk group from 37% to 68% in the validation data set. CONCLUSION The novel RAM stratified patients with cancer into a high-risk group with 8%-10% cumulative incidence of VTE and 7% PE/LE-DVT at 6 months (v 3% and 2%, respectively, in the low-risk group). The model had improved performance over the original KS and doubled the number of VTE events in the high-risk stratum. We encourage additional external validation from prospective studies.

Abstract 3173 Background: We evaluated the utility of screening for VTE using a previously developed clinical risk score (Khorana et al, Blood 2008) in a prospective cohort of cancer patients initiating outpatient chemotherapy but not receiving thromboprophylaxis. Methods: Cancer patients initiating a new chemotherapy regimen and deemed high-risk based on a predictive risk model (score ≥3) were enrolled on an ongoing prospective cohort study with informed consent. Patients were evaluated with baseline and Q4 (± 1) week serial ultrasonography for upto 16 weeks; additionally, computed tomography scans for restaging were also evaluated for VTE. Results: Of 30 patients enrolled on study, 8 (27%) developed a VTE. This included 5 patients with DVT alone (17%), 1 patient with PE alone (3%) and 2 (7%) with both. Twenty-seven patients underwent a baseline ultrasound. Of these, 3 asymptomatic DVTs were identified (11%). Subsequent ultrasounds were performed in 18 patients at week 4 (0 DVT), 17 patients at week 8 (0 DVT) and 15 patients at week 12 (1 DVT, 7%). An additional two patients developed symptomatic DVT between weeks 1 and 4. Restaging CT scans identified an asymptomatic PE in 1 patient at week 6 and asymptomatic PE in 1 patient at week 9 with subsequent symptomatic DVT at week 10. Conclusions: In a prospective observational study, 27% of cancer outpatients deemed high-risk using a clinical risk score developed VTE, a rate much higher than observed even in hospitalized acutely ill patients. Thus, this study confirms the validity of a previously described risk score. The role of thromboprophylaxis in this population is currently being tested. The value of screening ultrasonography should be considered in high-risk patients based on this risk score. Disclosures: No relevant conflicts of interest to declare.

Postoperative venous thromboembolic events (VTEs), such as lower extremity deep vein thrombosis (DVT), are major risk factors for gastric cancer (GC) patients following radical gastrectomy. Accurately predicting and managing these risks is crucial for optimal patient care. This retrospective case‒control study involved 693 GC patients from our hospital who underwent radical gastrectomy. We collected plentiful and comprehensive clinical indicators including a total of 49 baseline, preoperative, surgical and pathological clinical data. Using univariate logistic regression, we identified potential risk factors, followed by feature selection through the Boruta algorithm. We then constructed the final predictive model using multivariate logistic regression and evaluated it using receiver operating characteristic (ROC) curve analysis, calibration plots, decision curve analysis, and other methods. Additionally, we applied various machine learning techniques, including decision trees and random forests, to assess our model’s predictive strength. This retrospective case‒control study involved 693 GC patients from our hospital who underwent radical gastrectomy. We collected plentiful and comprehensive clinical indicators including a total of 49 baseline, preoperative, surgical and pathological clinical data. Using univariate logistic regression, we identified potential risk factors, followed by feature selection through the Boruta algorithm. We then constructed the final predictive model using multivariate logistic regression and evaluated it using receiver operating characteristic (ROC) curve analysis, calibration plots, decision curve analysis, and other methods. Additionally, we applied various machine learning techniques, including decision trees and random forests, to assess our model’s predictive strength. Univariate logistic analysis revealed 14 risk factors associated with postoperative lower limb DVT. Based on the Boruta algorithm, six significant clinical factors were selected, namely, age, D-dimer (D-D) level, low-density lipoprotein, CA125, and calcium and chloride ion levels. A nomogram was developed using the outcomes from the multivariate logistic regression analysis. The predictive model showed high accuracy, with an area under the curve of 0.936 in the training set and 0.875 in the validation set. Various machine learning algorithms confirmed its strong predictive capacity. MR analysis revealed meaningful causal relationships between key clinical factors and DVT risk. Based on various machine learning methods, we developed an effective predictive diagnostic model for postoperative lower extremity DVT in GC patients. This model demonstrated excellent predictive value in both the training and validation sets. This novel model is a valuable tool for clinicians to use in identifying and managing thrombotic risks in this patient population.

Gynecologic cancers are associated with high rates of venous thromboembolism (VTE), which is exacerbated by pelvic surgery and chemotherapy.

… risk of thrombosis compared with patients without cancer.In a … Individual prediction of VTE risk In an analysis of over 10,000 … , patients with cancer-associated thrombosis were more …

The pathological hypercoagulable state and associated risk of thrombosis in colorectal cancer (CRC) persist throughout the disease course. Accurate identification of patients at high risk of venous thromboembolism (VTE) and judiciously applying drug or mechanical prevention measures can significantly reduce the incidence of VTE. The review details a range of biomarkers, including platelet count, soluble P-selectin, D-dimer, and vascular endothelial growth factor (VEGF), which have been shown to correlate with increased VTE risk in CRC patients. In addition to the biomarker analysis, the review makes important recommendations for the routine monitoring of these biomarkers in CRC patients, especially those at higher risk for VTE. Furthermore, it discusses the integration of these biomarkers into clinical VTE risk prediction models, advocating for personalized and targeted thromboprophylaxis strategies. The review also explores future research directions, emphasizing the potential of antiplatelet and anticoagulant therapies in improving the prognosis of CRC patients by reducing thromboembolic events. This narrative review not only deepens our understanding of the molecular mechanisms driving cancer-associated thrombosis but also paves the way for novel therapeutic interventions aimed at preventing VTE in CRC patients.

Background Postoperative lower-extremity deep vein thrombosis (DVT) remains a clinically relevant complication after surgical resection for non-small cell lung cancer (NSCLC). This study aimed to identify factors associated with postoperative DVT and develop a nomogram for estimating DVT probability in patients undergoing NSCLC resection. Methods This retrospective cohort study included 328 patients with histologically confirmed NSCLC who underwent curative-intent pulmonary resection between January 2021 and December 2025. All patients underwent preoperative and postoperative lower-extremity duplex ultrasonography. The primary outcome was newly detected lower-extremity DVT within 30 days after surgery. Univariable and multivariable logistic regression analyses were performed to evaluate variables associated with postoperative DVT. A nomogram was developed, and model performance was assessed using receiver operating characteristic (ROC) analysis, bootstrap internal validation, and calibration analysis. Results Among the included patients, 136 were assigned to the postoperative DVT group and 192 to the non-DVT group. Most DVT events were diagnosed during the index hospitalization and were asymptomatic, isolated distal DVT. In the primary multivariable model, age ≥70 years (OR, 4.50; 95% CI, 1.21–17.85), diabetes mellitus (OR, 5.00; 95% CI, 1.16–22.55), adenocarcinoma histology (OR, 7.55; 95% CI, 1.80–30.44), and pathological stage III disease (OR, 5.16; 95% CI, 1.39–19.05) were independently associated with postoperative DVT. The nomogram showed an apparent area under the curve (AUC) of 0.896, with sensitivity of 86.15% and specificity of 91.25%. The bootstrap-corrected concordance index was 0.762, and the Hosmer–Lemeshow test showed no evidence of poor fit. Conclusions Age, diabetes mellitus, adenocarcinoma histology, and pathological stage III disease were associated with postoperative DVT in patients with resected NSCLC. The nomogram might support postoperative DVT risk estimation, but further external validation is warranted.

… cancer-associated VTE, cancer related thrombotic risk factors, and outcomes including mortality. Risk of cancer in VTE – risk of VTE in cancer … cancer being an independent predictor of …

Background Systemic activation of hemostasis is frequently observed in cancer patients, even in the absence of thrombosis. Moreover, this activation has been implicated in tumor progression, angiogenesis and metastatic spread. Increased levels of D-dimer, which is a degradation product of cross-linked fibrin, indicate a global activation of hemostasis and fibrinolysis. Design and Methods In a prospective and observational cohort study, we assessed the prognostic value of D-dimer levels for overall survival and mortality risk in 1178 cancer patients included in the Vienna Cancer and Thrombosis Study (CATS). Patients were followed over 2 years at regular intervals until occurrence of symptomatic venous thromboembolism or death. D-dimer levels were measured with a quantitative D-dimer latex agglutination assay Results The main solid tumors were malignancies of the lung (n=182), breast (n=157), lower gastrointestinal tract (n=133), pancreas (n=74), stomach (n=50), kidney (n=37), prostate (n=133), and brain (n=148); 201 of the patients had hematologic malignancies; 63 had other tumors. During a median follow-up of 731 days, 460 (39.0%) patients died. The overall survival probabilities for patients with D-dimer levels categorized into four groups based on the 1st, 2nd and 3rd quartiles of the D-dimer distribution in the total study population were 88%, 82%, 66% and 53% after 1 year, and 78%, 66%, 50% and 30% after 2 years, respectively (P<0.001). The univariate hazard ratio of D-dimer (per double increase) for mortality was 1.5 (95% confidence interval: 1.4–1.6, P<0.001) and remained increased in multivariable analysis including tumor subgroups, age, sex and venous thromboembolism. Conclusions High D-dimer levels were associated with poor overall survival and increased mortality risk in cancer patients.

Pancreatic cancer (PC) is a devastating malignancy with fewer than 10% of patients being alive at 5 years after diagnosis. Venous thromboembolism (VTE) occurs in approximatively 20% of patients with PC, resulting in increased morbidity, mortality and significant health care costs. The management of VTE is particularly challenging in these frail patients. Adequate selection of the most appropriate anticoagulant for each individual patient according to the current international guidelines is warranted for overcoming treatment challenges. The International Initiative on Thrombosis and Cancer multi-language web-based mobile application (downloadable for free at www.itaccme.com) has been developed to help clinicians in decision making in the most complex situations. In this narrative review, we will discuss the contemporary epidemiology and burden of VTE in PC patients, the performances and limitations of current risk assessment models to predict the risk of VTE, as well as evidence from recent clinical trials for the primary prophylaxis and treatment of cancer-associated VTE that support up-dated clinical practice guidelines.

Pulmonary lymphangitic carcinomatosis (PLC) is a well-known form of tumour metastasis to the pulmonary lymphatic system or to the adjacent interstitial tissue resulting in thickening of the bronchovascular bundle and septa. Another type of tumour metastasis to the lung involves the pulmonary vascular system and is known as pulmonary tumour thrombotic microangiopathy (PTTM). In this article, we will describe the unusual case of a young Chinese woman with gastric adenocarcinoma revealed by atypical radiographic lesions consistent with both PLC and PTTM. We will discuss the existing evidence and hypotheses about the pathophysiology of both conditions.

Supplemental Digital Content is available in the text. Objective: Pancreatic cancer activates coagulation and increases risk of venous thromboembolism (VTE). We aimed at characterizing the association of hemostatic biomarkers and VTE with mortality and chemotherapy response. Approach and Results: Pancreatic cancer patients (N=145) were included in a prospective, observational cohort study (CATS [Vienna Cancer and Thrombosis Study]). Hemostatic biomarkers (D-dimer, extracellular vesicle–tissue factor activity, prothrombin fragment 1+2, fibrinogen, factor VIII, PAI-1 [plasminogen activator inhibitor 1], sP-selectin [soluble P-selectin], thrombin generation assay) were measured at inclusion. The impact of VTE on overall survival/progression-free survival (OS/PFS) was evaluated by multistate modeling. The association of biomarkers with OS was analyzed by Cox-regression and with PFS and disease control rate in patients initiating palliative chemotherapy (n=95) by Cox-regression and logistic regression. Multivariable analysis included stage, grade, sex, age, performance status, VTE (time-dependent), vascular infiltration/compression, and tumor marker levels (carbohydrate-antigen 19-9, carcinoembryonic antigen). VTE occurrence was associated with shorter OS (transition hazard ratio, 3.40 [95% CI, 2.05–5.64]) and shorter PFS (transition hazard ratio, 2.10 [1.16–3.79]). Median post-VTE OS/PFS in months was 5.5 [2.2–6.5] and 3.0 [1.5–3.9], compared with 13.4 [9.7–16.6] and 7.5 [5.9–9.8] in patients without VTE (both P<0.001). D-dimer, extracellular vesicle–tissue factor activity, PAI-1, and sP-selectin were associated with increased mortality (hazard ratio per doubling, 1.27 [1.00–1.61]; 1.63 [1.14–2.36]; 1.25 [1.06–1.47]; 1.52 [1.05–2.20]). In patients initiating palliative chemotherapy, higher D-dimer predicted shorter PFS (hazard ratio per doubling, 1.27 [1.01–1.60]) and lower disease control rate (odds ratio per doubling, 0.59 [0.36–0.98]). Conclusions: VTE diagnosis is associated with shorter OS and PFS. Higher baseline levels of D-dimer, extracellular vesicle–tissue factor activity, PAI-1, and sP-selectin were independently prognostic for increased mortality, and D-dimer predicted response to palliative chemotherapy.

… A causal relationship between malignant cancer and thrombosis … thrombosis as the first manifestation of occult gastric cancer. The … Our data show that lung and pancreatic cancers were …

… thrombotic manifestations, and each showed particularly strong associations with cancers of the liver, lung, ovaries and pancreas… venous thrombosis was associated with cancer relative …

… venous thrombosis (EVT); intra-abdominal venous thrombosis (IVT); … In proximal type, the center of the thrombus was located in the … with pancreatic cancer. Thromb Res. 2017;150:30–2. …

Venous thromboembolism (VTE) is the second most common cause of mortality in cancer patients. The mechanisms of cancer-associated thrombosis (CAT), much like cancer itself, are multi-factorial and incompletely understood. Cancer type, stage, tumor-derived factors and genetics all affect CAT risk. Furthermore, cancer therapies as well as the indwelling vascular devices through which these therapies are delivered can increase the risk for CAT. In this review, we summarize mechanisms of hypercoagulability in cancer patients, patterns of thrombosis associated with cancer, current guidelines for the diagnosis and management of CAT, and important considerations regarding the placement of implantable vascular devices in the care of cancer patients with VTE.

Cancer-associated thrombosis (CAT) is a serious complication frequently observed in patients with cancer; however, its exact mechanism is not yet fully understood. Recent research in 2025 suggests that the lungs play a significant role in providing prothrombotic factors. Both primary and metastatic lung tumors have the potential to induce a state of hypercoagulability through various pathways, such as the secretion of procoagulant molecules, such as tissue factor (TF), triggering local inflammatory responses, platelet activation, and alterations in the function of vascular endothelial cells. Furthermore, the unique network of blood vessels and haemodynamic conditions in the lungs may contribute to the formation of thrombosis. Understanding the specific mechanisms by which lung cancer can lead to thrombosis is crucial for the early detection and intervention of CAT. This review delves into the intricate relationship between the tumor microenvironment in the lungs and the development of thrombosis, exploring the underlying molecular pathways involved in this relationship. By examining the prevention and treatment strategies for CAT currently used in clinical practice, with a focus on lung cancer-induced thrombosis, this review aims to establish a solid foundation for clinical management of these conditions. This review explores the relationship between lung cancer and thrombosis, focusing on the interaction of the tumor microenvironment, inflammatory factors, and coagulation abnormalities in creating a unique pathophysiological process in the lungs. Previous reviews have not addressed this specific aspect. By incorporating the latest research findings, this review suggests the use of lung-specific biomarkers for early detection, risk assessment, and personalized anticoagulant therapy for CAT. Emphasizing the potential benefits of combining anticoagulant therapy with cancer treatment by summarizing and analyzing existing researches, providing a comprehensive overview of an area that has been lacking in systematic reviews.

Abstract Aberrant factors associated with fibrinolysis and thrombosis are found in many cancer patients, which can promote metastasis and are associated with poor prognosis. The relationship between tumor-associated fibrinolysis and thrombosis is poorly understood in pancreatic cancer. This review provides a brief highlight of existing studies that the fibrinolysis and coagulation systems were activated in pancreatic cancer patients, along with aberrant high concentrations of tissue plasminogen activator (t-PA), urine plasminogen activator (u-PA), D-dimer, fibrinogen, or platelets. These factors cooperate with each other, propelling tumor cell shedding, localization, adhesion to distant metastasis. The relationship between thrombosis or fibrinolysis and cancer immune escape is also investigated. In addition, the potential prevention and therapy strategies of pancreatic cancer targeting factors in fibrinolysis and coagulation systems are also been discussed, in which we highlight two effective agents aspirin and low-molecular weight heparin (LMWH). Summarily, this review provides new directions for the research and treatment of pancreatic cancer.

… affecting patients with gastrointestinal cancers but increased DVT incidences have also been … FG cells, a pancreatic adenocarcinoma cell line with lower metastatic potential (compared …

… of venous thrombosis associated with pancreatic malignancies we followed a cohort of patients with pancreatic cancer (… Lung cancer, prostate cancer, colon cancer and haematological …

Patients with pancreatic cancer have a very high risk of both venous and arterial thrombosis compared with other cancers, caused by a tumour-driven hypercoagulable state. Better understanding of pancreatic cancer-associated prothrombotic and proinflammatory mechanisms opens the door to controlling prothrombotic states, ideally, without affecting the overall haemostasis. This narrative review brings together currently available evidence on epidemiology and pathogenesis of thrombotic complications in pancreatic adenocarcinoma. We describe risk factors for thrombosis and established and novel mechanisms of hypercoagulability. Among novel pathways of hypercoagulability, the release of neutrophils extracellular traps (NETs) by activated neutrophils and the crucial role of extracellular vesicles (EV) in participating in platelet and coagulation activation were described. We also reported recent evidence on EV role in thrombin generation amplification through the activation of the intrinsic pathway, discussing potential molecules implicated in this process.

Abstract Pancreatic ductal adenocarcinoma (PDAC) is an aggressive type of cancer and has a poor prognosis. Patients with PDAC are at high risk of developing thromboembolic events, which is a leading cause of morbidity and mortality following cancer progression. Plasma-derived coagulation is the most studied process in cancer-associated thrombosis. Other blood components, such as platelets, red blood cells, and white blood cells, have been gaining less attention. This narrative review addresses the literature on the role of cellular components in the development of venous thromboembolism (VTE) in patients with PDAC. Blood cells seem to play an important role in the development of VTE. Altered blood cell counts, i.e., leukocytosis, thrombocytosis, and anemia, have been found to associate with VTE risk. Tumor-related activation of leukocytes leads to the release of tissue factor-expressing microvesicles and the formation of neutrophil extracellular traps, initiating coagulation and forming a scaffold for thrombi. Tissue factor-expressing microvesicles are also thought to be released by PDAC cells. PDAC cells have been shown to stimulate platelet activation and aggregation, proposedly via the secretion of podoplanin and mucins. Hypofibrinolysis, partially explained by increased plasminogen activator inhibitor-1 activity, is observed in PDAC. In short, PDAC-associated hypercoagulability is a complex and multifactorial process. A better understanding of cellular contributions to hypercoagulability might lead to the improvement of diagnostic tests to identify PDAC patients at highest risk of VTE.

It has long been recognised that pancreatic cancer induces a hypercoagulable state that may lead to clinically apparent thrombosis. Although the relationship between pancreatic cancer and hypercoagulability is well described, the underlying pathological mechanism(s) and the interplay between these pathways remain a matter of intensive study. This review summarises existing data on epidemiology and pathogenesis of thrombotic complications in pancreatic cancer with a particular emphasis on novel pathophysiological pathways. Pancreatic cancer is characterised by high tumoural expression of tissue factor, activation of leukocytes with the release of neutrophil extracellular traps, the dissemination of tumour-derived microvesicles that promote hypercoagulability and increased platelet activation. Furthermore, other coagulation pathways probably contribute to these processes, such as those that involve heparanase, podoplanin and hypofibrinolysis. In the era in which heparin and its derivatives—the currently recommended therapy for cancer-associated thrombosis—might be superseded by direct oral anticoagulants, novel data from mouse models of cancer-associated thrombosis suggest the possibility of future personalised therapeutic approaches. In this dynamic era for cancer-associated thrombosis, the discovery of novel prothrombotic and proinflammatory mechanisms will potentially uncover pharmacological targets to prevent and treat thrombosis without adversely affecting haemostasis.

Background The hypercoagulable state of cancer patients is associated with their high mortality rate. Coagulation indicators may have an important role in the prognosis of gastric cancer patients and deserve to be explored in various aspects. Objective We conducted a meta-analysis to explore the correlation between coagulation and prognosis of gastric cancer. Methods A comprehensive systematic search was conducted in PubMed, Embase, Web of Science databases, and the Cochrane Library up to February 16, 2024. Literature screening and data extraction were performed by two independent reviewers. The processed data we pooled using either a random-effects model or a fixed-effects model and finally described overall survival with a risk ratio (hazard ratio [HR]) and predicted the likelihood of different clinicopathological events with a dominance ratio (OR). Results A total of 64 studies were screened for inclusion in the data analysis. Performing a meta-analysis of three indicators we derived that the risk of d-dimer (D-D), fibrinogen (FIB), and platelets (PLTs) were: HR = 1.85 (95% confidence interval [CI]: 1.59–2.15, N = 15), HR = 1.77 (95% CI: 1.57–1.99, N = 28), HR = 1.16 (95% CI: 1.12–1.21, N = 29). In addition to this, all three were associated with advanced clinicopathological stage (D-D: OR = 2.25, FIB: OR = 2.07, PLT: OR = 1.84), T stage (D-D: OR = 2.30, FIB: OR = 2.38, PLT: OR = 2.22) and lymph node metastasis (D-D: OR = 1.79, FIB: OR = 1.70, PLT: OR = 1.51). Conclusion Overall, the findings suggest that the three indicators, D-D, FIB, and PLT count, have significant predictive value for the prognosis of gastric cancer. They were associated with an advanced clinicopathological stage and a high risk of lymph node metastasis.

… The effect of thrombosis timing on pancreatic cancer-specific survival has never been … -adjusted dalteparin in patients with advanced or metastatic pancreatic cancer (APC): a multicentre…

Advanced gastric cancer is one of the most thrombogenic neoplasms. However, genetic mechanisms underlying this complication remain obscure, and the molecular and histological heterogeneity of this neoplasm hinder the identification of thrombotic biomarkers. Therefore, our main objective was to identify genes related to thrombosis regardless of Lauren subtypes. Furthermore, in a secondary exploratory study, we seek to discover thrombosis-associated genes that were specific to each TCGA molecular subtype. We designed a nested case-control study using the cohort of the AGAMENON national advanced gastric cancer registry. Ninety-seven patients were selected—48 with and 49 without venous thromboembolism (using propensity score matching to adjust for confounding factors)—and a differential gene expression array stratified by Lauren histopathological subtypes was carried out in primary tumor samples. For the secondary objective, the aforementioned differential expression analysis was conducted for each TCGA group. Fifteen genes were determined to be associated with thrombosis with the same expression trend in both the intestinal and diffuse subtypes. In thrombotic subjects, CRELD1, KCNH8, CRYGN, MAGEB16, SAA1, ARL11, CCDC169, TRMT61A, RIPPLY3 and PLA2G6 were underexpressed (adjusted-p < 0.05), while PRKD3, MIR5683, SDCBP, EPS8 and CDC45 were overexpressed (adjusted-p < 0.05), and correlated, by logistic regression, with lower or higher thrombotic risk, respectively, in the overall cohort. In each TCGA molecular subtype, we identified a series of genes differentially expressed in thrombosis that appear to be subtype-specific. We have identified several genes associated with venous thromboembolism in advanced gastric cancer that are common to Lauren intestinal and diffuse subtypes. Should these genetic factors be validated in the future, they could be complemented with existing clinical models to bolster the ability to predict thrombotic risk in individuals with advanced gastric adenocarcinoma.

Thrombosis remains a major cause of morbidity and mortality in cancer patients. Existing risk models fail to reliably predict venous thromboembolism (VTE), underscoring the need for more accurate predictive models. In this study, we conducted a high-throughput proteomic analysis of 1,105 plasma proteins from newly diagnosed lung and gastric cancer patients prospectively monitored for VTE development. Utilizing a Bayesian probabilistic machine learning approach, we developed a predictive model incorporating 11 protein biomarkers and five clinical parameters (age, sex, history of VTE, body mass index, and hemoglobin), which significantly outperformed the Khorana prediction model. Orthogonal validation in an external placebo cohort from a phase III trial confirmed the model’s predictive power. Further investigation into the mechanistic role of CD200 receptor 1 (CD200R1), a checkpoint receptor limiting leukocyte inflammatory response that contributed strongly to the model, showed that reduced concentrations in plasma correlated with higher D-dimer and thrombosis risk. In CD200R1-deficient mice, elevated thrombin-antithrombin complexes confirmed a prothrombotic state characterized by increased interleukin-17A (IL-17A) and endothelial inflammation. Administration of anti-IL-17A antibodies to CD200R1 deficient mice normalized thrombin generation in vivo, and a meta-analysis of human clinical IL-17A inhibitory antibody studies confirmed antithrombotic activity. These findings improve the prediction of thrombosis in cancer and highlight the utility of plasma proteomics to identify unanticipated mechanistic insights and therapeutic targets in thrombo-inflammatory disease.

The plasma levels of pro- and anticoagulant proteins are important markers for venous thrombosis (VT) risk and can be affected by both genetic and acquired factors, including cancer. Generally, these markers are measured using activity- or antibody-based assays. Targeted proteomics with stable-isotope-labeled internal standards has proven adept at the rapid, multiplex, and precise quantification of proteins in complex biological samples such as plasma. We used liquid chromatography coupled to multiple reaction monitoring (MRM) mass spectrometry to evaluate the concentrations of 31 coagulation- and fibrinolysis-related proteins in plasma from 25 healthy controls, 25 patients with VT, and 25 patients with VT who were also diagnosed with cancer. The concentration level of 1 to 3 proteotypic peptides per protein was determined, and all samples were previously characterized using traditional antibody- or activity-based methods. When comparing the conventional and the MRM strategies, the mean Pearson correlation for the 13 proteins (covered by 36 target peptides) shared between the 2 approaches was 0.77, indicating a good correlation. Additionally, MRM offers higher sensitivity (mean regression slope, 0.81), higher multiplicity in a single run, and good ability to leverage all measurements to discriminate groups using unsupervised clustering, which identified vitamin K antagonist users as well as patients with VT and cancer. The data collected using MRM show that the combination of coagulation factor levels yields signature information on VT and cancer, which was not obvious from a single measurement. These results encourage the further validation and investigation of MRM in profiling protein signature of disease.

Comprehensive protein analyses of plasma are made possible by high-throughput proteomic screens, which may help find new therapeutic targets and diagnostic biomarkers. Patients with cancer are frequently affected by venous thromboembolism (VTE). The limited predictive accuracy of current VTE risk assessment tools highlights the need for new, more targeted biomarkers. Although coagulation biomarkers for the diagnosis, prognosis, and treatment of VTE have been investigated, none of them have the necessary clinical validation or diagnostic accuracy. Proteomics holds the potential to uncover new biomarkers and thrombotic pathways that impact the risk of thrombosis. This review explores the fundamental methods used in proteomics and focuses on particular biomarkers found in VTE and cancer-associated thrombosis.

Simple Summary The risk of venous thromboembolism in cancer is nine times higher than in the general population and the second leading cause of death in these patients. Tissue factor and downstream plasmatic coagulation cascade are largely responsible for the risk of thrombosis in cancer. In recent years, it has been increasingly recognised that platelets also play a central role in tumour growth and cancer-associated thrombosis. The underlying molecular mechanisms are largely unknown. In order to comprehensively investigate the biochemical changes in platelets from cancers with high risk of thrombosis, we examined the platelet proteome of brain and lung cancer patients in comparison to sex and age-matched healthy controls. However, we only found alterations in lung cancer, where some of these platelet proteins directly promote thrombosis. One example is the increased amount of the enzyme protein disulfide isomerase, which is clinically investigated as an antithrombotic drug target of the plant-based flavonol quercetin. Abstract In order to comprehensively expose cancer-related biochemical changes, we compared the platelet proteome of two types of cancer with a high risk of thrombosis (22 patients with brain cancer, 19 with lung cancer) to 41 matched healthy controls using unbiased two-dimensional differential in-gel electrophoresis. The examined platelet proteome was unchanged in patients with brain cancer, but considerably affected in lung cancer with 15 significantly altered proteins. Amongst these, the endoplasmic reticulum (ER) proteins calreticulin (CALR), endoplasmic reticulum chaperone BiP (HSPA5) and protein disulfide-isomerase (P4HB) were significantly elevated. Accelerated conversion of the fibrin stabilising factor XIII was detected in platelets of patients with lung cancer by elevated levels of a coagulation factor XIII (F13A1) 55 kDa fragment. A significant correlation of this F13A1 cleavage product with plasma levels of the plasmin–α-2-antiplasmin complex and D-dimer suggests its enhanced degradation by the fibrinolytic system. Protein association network analysis showed that lung cancer-related proteins were involved in platelet degranulation and upregulated ER protein processing. As a possible outcome, plasma FVIII, an immediate end product for ER-mediated glycosylation, correlated significantly with the ER-executing chaperones CALR and HSPA5. These new data on the differential behaviour of platelets in various cancers revealed F13A1 and ER chaperones as potential novel diagnostic and therapeutic targets in lung cancer patients.

Cancer patients have an eleven-fold increased risk of venous thromboembolism (VTE) compared to the general population. In this hypothesis-generating study we investigated plasma protein levels in colorectal cancer patients with and without thrombosis using targeted absolute quantification of 269 plasma proteins. We included samples from 142 patients with stage III/IV colorectal cancer from MICA - a multinational prospective cohort study, and from 98 patients from CATS - a prospective cohort study with stage III/IV colorectal cancer. The primary outcome was objectively confirmed symptomatic or incidental deep vein thrombosis or pulmonary embolism during a 6-month follow-up period. In MICA, 11 (7.7%) developed VTE; in CATS 6 patients (6.1%) developed VTE within 6 months, and 10 (10.2%) within 2 years. Six differentially abundant proteins (DAPs) were identified in MICA: APOB100, CD5L, IGHG1, IGHM, PRG4, and TF. A model using these six proteins achieved a c-statistic of 0.687 (95% CI: 0.658-0.717) by internal cross-validation with 100 repeats and random 80% training sets. The optimism-corrected c-statistics was 0.675 (95% CI: 0.648-0.701). Using any subset of the DAPs yielded a c-statistics >0.67, with the best model reaching 0.768 (95% CI: 0.746-0.790). This outperformed the Khorana, modified-Vienna, PROTECHT, and CONKO models. The six DAPs had also predictive value in CATS with c-statistics at 0.70 (95% CI:0.671-0.728) for the 6-month, and 0.73 (95% CI:0.702-0.728) for 2-year follow-up. Two proteins showed inverted patterns between cohorts, likely due to chemotherapy. Our findings call for further investigation into the proteins identified, warranting further validation in larger, standardized studies.

Background: Existing risk models for cancer-associated thrombosis (CAT) show suboptimal performance in selective high-risk populations with cancer. Affinity-based plasma proteomics offer a novel approach for detecting CAT risk. Objectives: To identify plasma biomarkers for CAT using proximity extension assays in an advanced cancer cohort. Patients/Methods: We performed a nested case-control study using the Olink Explore HT panel. The final cohort included 57 patients with CAT and 113 matched control patients from five selected cancer types who had samples collected between cancer diagnosis and chemotherapy initiation. Random survival forest model was used to assess non-linear associations with CAT in 5,416 normalized protein expressions and 8 clinical variables. Evaluation metrics averaged across bootstrapped out-of-bag test sets included time-dependent receiver operation characteristic curve (TD-ROC), calibration plot, and cumulative incidence in high- versus low-risk predicted groups. We used SHapley Additive exPlanation (SHAP) for feature interpretability. We performed overrepresentation analysis (ORA) and gene set enrichment analysis (GSEA) to assess biological pathway plausibility. Results: Our internally validated model predicted early thrombotic events well (TD-ROC 0.83 at 30 days and 0.73 at 90 days), but the discrimination waned with follow-up time (0.67 at 180 days). Calibration followed a similar pattern. In ORA and GSEA, important proteins were observed in hemostatic pathways including platelet activation, fibrin clot formation, and complement cascade regulation. Conclusion: Affinity-based plasma proteomics can be used as a novel strategy to identify biomarkers of CAT. External validation with larger sample size in a cohort setting is required for risk prediction models.

Objective Non-small cell lung cancer (NSCLC) patients present a high incidence of venous thromboembolism (VTE) with poor prognosis. It is crucial to identify and diagnose VTE early. The study aimed to identify potential protein biomarkers and mechanism of VTE in NSCLC patients via proteomics research. Methods Proteomic analysis of the human plasma was performed through data-independent acquisition mass spectrometry for 20 NSCLC patients with VTE, and 15 NSCLC patients without VTE. Significantly differentially expressed proteins were analyzed by multiple bioinformatics method for further biomarker analysis. Results A total of 280 differentially expressed proteins were identified in VTE and non-VTE patients, where 42 were upregulated and 238 were downregulated. These proteins were involved in acute-phase response, cytokine production, neutrophil migration and other biological processes related to VTE and inflammation. Five proteins including SAA1, S100A8, LBP, HP and LDHB had significant change between VTE and non-VTE patients, with the area under the curve (AUC) were 0.8067, 0.8308, 0.7767, 0.8021, 0.8533, respectively. Conclusions SAA1, S100A8, LBP, HP and LDHB may serve as potential plasma biomarkers for diagnosis VTE in NSCLC patients.

… We studied their impact on plasma protein profiles in cancer patients, … for cancer-associated thrombosis (CAT)1,2, 4 emerging evidence suggests that ICIs may also increase thrombotic …

Introduction Clinical risk assessment scores can help risk-stratify patients for cancer-associated thrombosis (CAT); however, their performance in individual cancer subtype remains suboptimal. While previous studies have explored the utility of single plasma biomarkers such as D-dimer or P-selectin, we lack a validated, non-invasive biomarker signature panel. Our current study evaluates a plasma proteomic assay and machine learning model for predicting CAT. Methods We performed a nested case control study from 1,694 patients with newly diagnosed solid tumor malignancy who had plasma sample collection from 2011-2023 at the Harris Health System. Patients with early-stage disease, samples taken before cancer diagnosis or after chemotherapy initiation, or inadequate follow-up were excluded. Five common cancer types were selected (breast, colorectal, lung, pancreatic, gastroesophageal) to form an eligible cohort of 312 patients. Incidence density sampling was used with 1:2 matching on cancer type, stage, and treatment to form a final analytic cohort of 170 patients (57 CAT vs 113 controls). We performed proteomic profiling using the Olink Explore HT, which uses the proximity extension assay to measure plasma proteins as normalized protein expression (NPX) values. Random Survival Forest (RSF) model was used to predict time to CAT, where NPX values (5,416 proteins) and clinical variables (age, sex, race, ethnicity, cancer type, stage, diagnosis year) were trained in 100 bootstrapped iterations with resample. Internal validation with time dependent receiver operating characteristic (TD-ROC) was assessed at days 30, 90, and 180, using out-of-bag (OOB) test samples. Top proteins identified by nonparametric permutation variable importance (VIMP) and stably present in multiple iterations were retained for pathway enrichment analysis using the Reactome Over-Representation Analysis with p-value <0.05 and FDR q-value <0.1. Results Among 170 patients, the median age was 54 (IQR 47-60), 64% were female. Race and ethnicity included 62% Hispanic, 12% Non-Hispanic (NH) White, 18% NH Black, and 7% NH Asian. There were 42 breast, 51 colorectal, 35 lung, 22 pancreatic, and 20 gastroesophageal cancers; 53% were metastatic; and all received chemotherapy after sample collection. The 57 CAT events included 23 pulmonary embolism, 12 lower extremity deep vein thrombosis (DVT), 18 upper extremity DVT, and 4 splanchnic vein thrombosis. Median time to CAT was 154 days (IQR 70-262). There were 7, 19, and 31 events by 30, 90, and 180 days, respectively. Among 5,416 proteins, the NPX values ranged from -11.43 to +12.40 (IQR -0.50 to +0.52). There were no significant differences by batch or storage time. For internal validation, the RSF model achieved a bootstrapped mean TD-ROC of 0.82 (95% CI 0.54-0.98), 0.71 (95% CI 0.57-0.88), and 0.67 (95% CI 0.56-0.79) at 30, 90, and 180 days, respectively. Approximately 35% were classified as high-risk. In the OOB test sets, the observed average VTE incidence in the high-risk group were 13%, 21%, and 26% at 30d, 90d, and 180d, respectively. In comparison, the observed average VTE incidence in the low-risk group was 1%, 8%, and 15% at the same time points. Top important proteins included KANK1, F9, CABP4, PRND, and GFPT2, among others. In pathway enrichment analyses, the top 20% proteomic features were over-represented in neutrophil degranulation, extracellular matrix organization, platelet cytosolic calcium and degranulation, integrin cell surface interactions, regulation of complement cascade, and formation of fibrin clot. Conclusion Individual cancer patients have unique prothrombotic expression profiles in the plasma that are prognostic for future CAT occurrence. As demonstrated in the pathway enrichment analyses from the top RSF features, the relationship between coagulation cascade, neutrophil, platelet, complement, and extracellular matrix is complex and non-linear. A survival tree-based machine learning model incorporating all plasma proteomic signatures can predict short-term CAT occurrence with higher accuracy than long-term (0.82 vs 0.67). Instead of single target assays, panel-based plasma proteomic assays may complement existing clinical risk scores and further differentiate the thrombotic risk profiles among individual cancer subtypes. External and prospective cohort validations are needed to ensure reproducibility and generalizability.

… Another study detected plasma proteomics and revealed a total of 197 DEPs in ovarian cancer … , and a higher risk of thrombotic events; moreover, platelets can also promote ovarian …

Deep vein thrombosis (DVT) is a leading cause of morbidity and mortality after trauma. Here, we integrate plasma metabolomics and proteomics to evaluate the metabolic alterations and their function in up to 680 individuals with and without DVT after trauma (pt-DVT). We identify 28 metabolites and 2 clinical parameter clusters associated with pt-DVT. Then, we develop a panel of 9 metabolites (hexadecanedioic acid, pyruvic acid, L-Carnitine, serotonin, PE(P-18:1(11Z)/18:2(9Z,12Z)), 3-Hydroxycapric acid, 5,6-DHET, 3-Methoxybenzenepropanoic acid and pentanenitrile) that can predict pt-DVT with high performance, which can be verified in an independent cohort. Furthermore, the integration analysis of metabolomics and proteomics data indicates that the upregulation of glycolysis/gluconeogenesis-TCA cycle may promote thrombosis by regulating ROS levels in red blood cells, suggesting that interfering with this process might be potential therapeutic strategies for pt-DVT. Together, our study comprehensively delineates the metabolic and hematological dysregulations for pt-DVT, and provides potential biomarkers for early detection. Deep vein thrombosis after trauma (pt-DVT) patients undergo metabolic changes but a comprehensive characterization in humans is lacking. Here the authors integrate metabolome and proteome to reveal pt-DVT-related metabolic alterations and their function, and reveal potential biomarkers.

Pancreatic cancer patients are at risk for venous thromboembolism (VTE); the value of thromboprophylaxis has not been definitively established.

Background: The cancer is associated with a state of hypercoagulability, which may be the cause of venous thromboembolism (VTE), representing an undeniable cause of morbidity and mortality. Our study aimed to investigate the role of hypercoagulability markers (D-dimers, microparticles, and V Leiden mutation) in predicting cancer-associated VTE. Methods: A prospective cohort study was conducted among cancer patients who will receive chemotherapy in the Medical Oncology and Hematology departments of the EHU of Oran, Algeria from February 2013 to May 2015, followed by an observation period of two years. First, we evaluated the risk of cancer-related VTE by hypercoagulability parameters (D-dimers, microparticles, V Leiden mutation). In the second step, we tested the predictive value of the Khorana risk score (KRS) of cancer-related VTE. Then, we developed and tested the predictive value of an expanded score based on the addition of predictive biomarkers to the KRS parameters. Results: A total of 165 patients were included in our study whose median age was 62 years. More than half were males (52.7%). After an observation period of 2 years, ten patients (6.0%) developed a VTE. Among the criteria studied, only the D-dimers and the microparticles were predictive of VTE in cancer. The positive predictive value (PPV) of the KRS was 13.6%, and the negative predictive value (NPV) was 97.9%. After adding two predictive biomarkers (D-dimers and microparticles), the expanded score had a better predictive value with a PPV of 23.5% and a VPN of 98.6%. Conclusion: The addition of hypercoagulability biomarkers (microparticles and D-dimers) to the routine clinical and biological parameters of the KRS enhances the predictive potential of VTE risk in cancer.

Hospitalized patients with COVID‐19 have increased risks of venous (VTE) and arterial thromboembolism (ATE). Active cancer diagnosis and treatment are well‐known risk factors; however, a risk assessment model (RAM) for VTE in patients with both cancer and COVID‐19 is lacking.

Venous thromboembolism (VTE) is a preventable disease, thus, in a number of clinical situations primary thromboprophylaxis has been proposed. Although we now know that cancer is one of the most important risk factors for VTE, primary prophylactic anticoagulation is only widely established for high-risk hospitalized patients and peri- and postoperatively after major cancer surgery. Long-term primary thromboprophylaxis in ambulatory cancer patients has been demonstrated to be effective. However, drawbacks are the additional burden of drug use, the lack of a reduced mortality benefit and costs. Only with reliable risk prediction the recommendation of primary thromboprophylaxis will convince oncologists and patients of its usefulness. This review deals with clinical and laboratory parameters and their combination in risk assessment models to define patients at high and low risk of VTE, in whom targeted thromboprophylaxis could best be applied. At present 90% of patients in the so-called intermediate- to high-risk group according to the Khorana score still do not develop VTE during the first 6 months, whereas there is a high absolute number of patients in the so-called low-risk groups that develop VTE. Improvements in risk assessment have been made by new risk prediction models. However, additional refinements to further improve risk prediction and their applicability in clinical practice are still needed.

… the variables of the Khorana model and adds sP-selectin and D-dimer levels, was … Khorana score, as are the PPV and the NPV; the specificity is similar to that of the Khorana score…

Objective This study aimed to investigate a suitable risk assessment model to predict deep vein thrombosis (DVT) in patients with gynecological cancer. Methods Data from 212 patients with gynecological cancer in the Affiliated Tumor Hospital of Guangxi Medical University were retrospectively analyzed. Patients were risk-stratified with three different risk assessment models individually, including the Caprini model, Wells DVT model, and Khorana model. Results The difference in risk level evaluated by the Caprini model was not different between the DVT and control groups. However, the DVT group had a significantly higher risk level than the control group with the Wells DVT or Khorana model. The Wells DVT model was more effective for stratifying patients in the DVT group into the higher risk level and for stratifying those in the control group into the lower risk level. Receiver operating curve analysis showed that the area under the curve of the Wells DVT, Khorana, and Caprini models was 0.995 ± 0.002, 0.642 ± 0.038, and 0.567 ± 0.039, respectively. Conclusion The Wells DVT model is the most suitable risk assessment model for predicting DVT. Clinicians could also combine the Caprini and Wells DVT models to effectively identify high-risk patients and eliminate patients without DVT.

… The expanded Khorana risk model applied a D-dimer threshold representing the 75th … consider D-dimer levels of the 182 lung cancer patients within the Vienna Cancer and Thrombosis …

BACKGROUND Malignancy predisposes patients to higher risk of venous thromboembolism (VTE), which is the second leading cause of death in patients with cancer. OBJECTIVE This narrative review evaluates VTE in malignancy and the emergency medicine investigation and management of this patient population. DISCUSSION Patients with malignancy are at higher risk of VTE, including deep venous thrombosis (DVT) and pulmonary embolism (PE). Risk factors include the underlying cancer, other hematologic disorders, cancer therapies, and underlying comorbidities. While patients with malignancy and VTE can present similarly to those without malignancy, incidental VTE is more common in cancer patients. Existing scores such as the Wells and Revised Geneva score can assist in risk stratification in patients with malignancy. A negative D-dimer result in the appropriately risk-stratified patient can be used to exclude VTE, though D-dimer is more commonly elevated at baseline in patients with malignancy. Several scoring systems may be useful to predict recurrent risk of VTE, including the Khorana and Ottawa scores. Treatment includes anticoagulation with direct oral anticoagulants (DOACs) or low molecular weight heparin (LMWH). Outpatient therapy may be appropriate in select patients. CONCLUSIONS This narrative review provides key updates in the assessment and management of cancer patients with VTE.

The frequency of venous thromboembolism (VTE) is rising in patients with cancer. VTE contributes to mortality and morbidity, but the risk for VTE can vary widely between individual patients. Clinical risk factors for VTE in cancer include primary site of cancer, use of systemic therapy, surgery, and hospitalization. Biomarkers predictive of VTE include platelet and leukocyte counts, hemoglobin, D-dimer, and tissue factor. A recently validated risk model incorporates 5 easily available variables and can be used clinically to identify patients at increased risk of VTE. In high-risk settings, including surgery and hospitalization, thromboprophylaxis with either unfractionated heparin or low-molecular-weight heparins has been shown to be safe and effective. Recent studies have also suggested a potential benefit for thromboprophylaxis in the ambulatory setting, although criteria for selecting patients for prophylaxis are not currently well defined. This article focuses on recent and ongoing studies of risk assessment and prophylaxis in patients with cancer.

… Elevated D-dimer levels are shown to be associated with recurrent VTE in cancer patients (… are at increased risk for venous thromboembolism (VTE) with a Khorana score of 2 or higher. …

Simple Summary Cancer patients are at greater risk of developing venous thromboembolism compared to the general population, which can lead to a decreased quality of life, a worsened prognosis, and increased treatment costs. Guidelines provide clear strategies for preventing thrombosis in hospitalized cancer patients and those undergoing surgery. For ambulatory cancer patients, thromboprophylaxis is recommended only for those who are at high risk. However, this can be challenging in clinical practice. The current guidelines do not provide sufficient information on this problem. Imaging and biomarker screening techniques are underutilized in practice. Although new risk scores, nomograms, and strategies have been developed using biomarkers and clinical and genetic features, many of these methods have not yet been validated. Machine learning algorithms have already been studied with promising results. This review presents the current knowledge on venous thromboembolism risk assessment in ambulatory cancer patient settings. Abstract Many cancer patients will experience venous thromboembolism (VTE) at some stage, with the highest rate in the initial period following diagnosis. Novel cancer therapies may further enhance the risk. VTE in a cancer setting is associated with poor prognostic, a decreased quality of life, and high healthcare costs. If thromboprophylaxis in hospitalized cancer patients and perioperative settings is widely accepted in clinical practice and supported by the guidelines, it is not the same situation in ambulatory cancer patient settings. The guidelines do not recommend primary thromboprophylaxis, except in high-risk cases. However, nowadays, risk stratification is still challenging, although many tools have been developed. The Khrorana score remains the most used method, but it has many limits. This narrative review aims to present the current relevant knowledge of VTE risk assessment in ambulatory cancer patients, starting from the guideline recommendations and continuing with the specific risk assessment methods and machine learning models approaches. Biomarkers, genetic, and clinical features were tested alone or in groups. Old and new models used in VTE risk assessment are exposed, underlining their clinical utility. Imaging and biomolecular approaches to VTE screening of outpatients with cancer are also presented, which could help clinical decisions.

BACKGROUND Guidelines recommend using risk assessment tools to identify ambulatory patients with cancer at high risk of venous thromboembolism (VTE). OBJECTIVE We aimed to validate a new cancer-associated thrombosis (CAT) risk score in a population-based healthcare setting. METHODS We used healthcare registry data and electronic medical records from the Central Denmark Region to calculate the new CAT risk score and the guideline-recommended Khorana score in patients with a first-time cancer diagnosis who initiated systemic cancer therapy. Patients were followed for six months after initiation of therapy. The outcome was any VTE identified through hospital discharge diagnoses. Discrimination was assessed using c-statistics. RESULTS We included 12,471 patients from 2012 through 2020. Of these, 416 (3.3%) developed VTE. The c-statistic was 0.71 (95% confidence interval [CI]: 0.68-0.74) for the new CAT score and 0.66 (95% CI: 0.63-0.70) for the Khorana score. The six-month cumulative VTE incidence was 5.0% in 6,175 patients classified as high risk by the new CAT score, compared with 1.7% in 6,296 patients classified as low risk. The six-month cumulative VTE incidence was 5.2% in 4,263 patients classified as high risk by the Khorana score, compared with 2.4% in 8,208 patients classified as low risk. CONCLUSION The new CAT score had a discriminatory ability similar to that reported in the derivation study. The c-statistic was numerically higher than that of the Khorana score. Our findings support implementation of the new CAT score to identify ambulatory patients with cancer who are at high risk of VTE.

Introduction Current clinical guidelines do not recommend the routine use of thromboprophylaxis in cancer primary unselected patients. Identifying cancer patients who could be beneficiaries of thrombotic prophylaxis is a real challenge. We aimed to analyse the application of Khorana score in cancer patients. We also tried to evaluate the prescription of primary thromboprophylaxis in cancer patients at risk of venous thromboembolic disease (VTED). Methods A retrospective observational study of survival of hospitalised patients diagnosed with pulmonary embolism (PE) at the Hospital Central de la Defensa from January 2009 to March 2018. They were stratified into tumour PE (TPE) and non-tumour PE (nTPE). A case-control study was also carried out by TPE patients and non PE cancer patients (nPEC). Results 108 patients were diagnosed with TPE, 260 nTPE and 324 nPEC. Gynaecological tumours were the most frequent (23.1%), followed by lung, digestive and urological cancer (20.4% each) in the TPE group. Death risk was 1.9 times higher in cancer patients (95% CI: 1.23–2.8) (p < 0.001). Khorana score was ≥3 points in 9.7% of TPE and 3.1% of nPEC compared to 26.2% of TPE and 9.9% of nPEC with Khorana score ≥2 points (p < 0.001). 7.4% of TPE patients received thromboprophylaxis. Khorana score in TPE patients without thromboprophylaxis was ≥3 points in the 9% and ≥2 points in the 24%. Conclusions There is an underutilisation of thromboprophylaxis in our cancer patients and mainly in those with high risk of VTED, as well as poor adherence to the Khorana score. More studies are needed to validate these findings and to optimise predictive strategies in the management of these patients.

BACKGROUND Risk assessment models (RAMs) are relevant approaches to identify cancer outpatients at high risk of venous thromboembolism (VTE). Among proposed RAMs, the Khorana (KRS) and the new-Vienna CATS risk scores have been externally validated in ambulatory cancer patients. OBJECTIVES To test KRS and new-Vienna CATS scores in 6-month VTE prediction and mortality in a large prospective cohort of metastatic cancer outpatients during chemotherapy. PATIENTS/METHODS Newly diagnosed patients with metastatic non-small cell lung, colorectal, gastric, or breast cancers were analyzed (n=1,286). Cumulative incidence of objectively confirmed VTE was estimated with death as a competing risk and multivariate Fine and Gray regression. RESULTS Within 6 months, 120 VTE events (9.7%) occurred. The KR and the new Vienna CATS scores showed comparable c-stat. Stratification by KRS provided VTE cumulative incidences of 6.2%, 11.4%, and 11.5% in the low-, intermediate-, and high-risk categories, respectively (p=ns), and of 8.5% vs 11.8% (p=ns) in the low- vs high-risk group by the single 2-point cut-off value stratification. Using a pre-defined 60 points cut-off by the new-Vienna CATS score, 6.6% and 12.2% cumulative incidences were obtained in the low- and high-risk group, respectively (p<0.001). Furthermore, having a KRS ≥2 or a new-Vienna CATS score >60 points was also an independent risk factor for mortality. CONCLUSIONS In our cohort, the 2 RAMs showed a comparable discriminating potential, however, after the application of cut-off values, the new-Vienna CATS score provided statistically significant stratification. Both RAMs proved to be effective in identifying patients at increased risk of mortality.

Background Although the Khorana venous thromboembolism (VTE) risk score (KRS) is well recognized as a simple VTE risk assessment method in patients with cancer, whether it is suitable for Asian populations is unclear. Objectives This study validated KRS for the prediction of VTE and investigated the value of the KRS in predicting mortality in Japanese patients with cancer. Methods A body mass index value of 25 kg/m2 or more was defined as obesity according to World Health Organization consensus. A total of 27,687 patients with cancer were subdivided into low- (0), intermediate- (1-2), and high-score (3) groups by the KRS. The primary and secondary endpoints were VTE and all-cause mortality, respectively. Results The prevalence of VTE was 1.7%, 7.3%, and 11.0% for low-, intermediate-, and high-score patients, respectively. Receiver operating characteristic (ROC) analysis showed that the KRS significantly predicted VTE (area under the curve, 0.679; 95% confidence interval [CI] 0.666-0.692; P < 0.001). The cutoff value for the KRS was 1.0. Logistic regression analysis demonstrated that the KRS was an independent predictor of VTE (odds ratio 1.766; 95% CI 1.673-1.865; P < 0.01). The cutoff value of the KRS for all-cause mortality determined by ROC analysis was 2.0. Kaplan–Meier analysis demonstrated a significantly higher incidence of mortality in the KRS ≥2 group than in the KRS 0-1 group (log-rank: P < 0.01). Conclusions The KRS was useful in Japanese patients with cancer and might be a potentially useful marker for the prediction of mortality. Establishing optimal scores for Japanese subjects is mandatory because of its low diagnostic ability. (KUMAMON Cancer registry; UMIN000047554)

… In contrast, the Khorana score assesses the risk of thrombosis in patients with cancer by … , the inclusion of BMI in the Khorana score may present limitations for those who have a low …

Several studies have suggested a role for blood coagulation proteins in tumour progression. Herein, we discuss (1) the activation of the blood clotting cascade in the tumour microenvironment and its impact on primary tumour growth; (2) the intravascular activation of blood coagulation and its impact on tumour metastasis and cancer-associated thrombosis; and (3) antitumour therapies that target blood-coagulation-associated proteins. Expression levels of the clotting initiator protein TF (tissue factor) have been correlated with tumour cell aggressiveness. Simultaneous TF expression and PS (phosphatidylserine) exposure by tumour cells promote the extravascular activation of blood coagulation. The generation of blood coagulation enzymes in the tumour microenvironment may trigger the activation of PARs (protease-activated receptors). In particular, PAR1 and PAR2 have been associated with many aspects of tumour biology. The procoagulant activity of circulating tumour cells favours metastasis, whereas the release of TF-bearing MVs (microvesicles) into the circulation has been correlated with cancer-associated thrombosis. Given the role of coagulation proteins in tumour progression, it has been proposed that they could be targets for the development of new antitumour therapies.

… activate the coagulation cascade. TF, the most potent initiator of coagulation, is variably expressed in many tumor … circulation as an alternatively spliced soluble protein [2] or associated …

Tumours are capable of activating blood coagulation through the expression of procoagulant molecules such as tissue factor, cancer procoagulant and hepsin. Initiation of the clotting cascade results in the generation of the activated serine proteases factor VIIa, factor Xa and thrombin. These proteases act via protease-activated receptors and tissue factor to alter gene expression, thereby modulating tumour cell growth, invasion, metastasis and angiogenesis.

… they activate. Finally, we will elaborate on the impact of tumorspecific coagulation factor … factor receptor (EGFRvIII) mutant elevated proteins belonging to the TF signaling pathways, …

… Although levels of protein C are significantly increased in cancer, tumor-induced coagulation activation results in hypercoagulability, particularly in disseminated malignancies [25], [39]. …

… been recognized showing that the tumor not only activates the coagulation system, but vice versa, activated coagulation proteins are able to induce molecular effects in tumor cells. The …

… generation or platelet activation) intravenously injected tumor cells will be kept … coagulation system in tumor metastases with special emphasis on a pivotal system of clotting activation…

… The coagulation cascade is linked to tumor growth and metastasis via its induction … -activated protein kinase (MAPK) activity induce positive regulation of TF expression by VEGF in tumor…

… If we can decrease the angiogenic capability of tumours and the … ordered phases of coagulation activation associated with net … TM presents protein C (an inhibitor of coagulation) for …

The progression of breast cancer from early-stage to metastatic disease results from a series of events during which malignant cells invade and travel within the bloodstream to distant sites, leading to a clonogenic accumulation of tumor cells in non-breast tissue. While mechanistically complex, an emerging literature supports hemostatic elements as an important patient factor that facilitates the metastatic potential of breast cancer. Hemostatic elements involved include platelets, coagulation, and fibrinolysis. Key steps in breast tumor progression, including cellular transformation, proliferation, tumor cell survival, and angiogenesis, can be mediated by components of the hemostatic system. Thus, the hemostatic system provides potential targets for novel therapeutic approaches to breast cancer therapy with drugs in current use and in development. The present article provides a comprehensive overview of the evidence and mechanisms supporting the roles played by platelets, coagulation activation, and the fibrinolytic system in breast cancer progression.

Cancer is a risk factor for venous thromboembolism (VTE) and plasma d‐dimer (DD) and tissue factor (TF) are established VTE associated markers. Circulating tumor cells (CTCs) are associated with the risk of VTE in metastatic breast cancer. This study aimed to correlate CTCs, blood coagulation and the urokinase plasminogen activator (uPA) system in primary breast cancer (PBC) patients. This prospective study included 116 PBC patients treated by primary surgery. CTCs were detected by quantitative RT‐PCR assay for expression of epithelial (CK19) or epithelial‐mesenchymal transition (EMT) genes (TWIST1, SNAIL1, SLUG, ZEB1, FOXC2). Plasma DD, TF, uPA system proteins were detected by enzyme‐linked immunosorbent assays, while expressions of uPA system in surgical specimens were evaluated by immunohistochemistry. CTCs were detected in 27.6% patients. Patients with CTCs had a significantly higher mean plasma DD (ng/mL) than those of patients without CTCs (632.4 versus 365.4, p = 0.000004). There was no association between plasma TF and CTCs. Epithelial CTCs exhibit higher expression of uPA system genes compared to EMT_CTCs. Patients with CTCs had higher plasma uPA proteins than those of patients without CTCs; there was no correlation between tissue expression of uPA system, CTCs, DD or TF levels. In multivariate analysis CTCs and patients age were independent factors associated with plasma DD. We found association between plasma DD and CTCs indicating a potential role for activation of the coagulation cascade in the early metastatic process. CTCs could be directly involved in coagulation activation or increased CTCs could be marker of aggressive disease and increased VTE risk.

… that activated platelets synthesize a wide range of proteins, … -charged surface for harboring coagulation factor complexes, and … Activated platelets also support the intrinsic coagulation in …

… promotes spread of tumors and is thus … tumor cells strongly accelerate plasma coagulation as a result of: (i) expression of the blood clotting initiator protein, TF, and (ii) direct activation of …

The putative role of tissue factor (TF) as a receptor involved in signal transduction is indicated by its sequence homology to cytokine receptors (Bazan, J. F. (1990) Proc. Natl. Acad. Sci. U. S. A. 87, 6934–6938). Signal transduction induced by binding of FVIIa to cells expressing TF was studied with baby hamster kidney (BHK) cells stably transfected with TF and with a reporter gene construct encoding a luciferase gene under transcriptional control of tandem cassettes of signal transducer and activator of transcription (STAT) elements and one serum response element (SRE). FVIIa induced a significant luciferase response in cells expressing TF, BHK(+TF), but not in cells without TF. The BHK(+TF) cells responded to the addition of FVIIa in a dose-dependent manner, whereas no response was observed with active site-inhibited FVIIa, which also worked as an antagonist to FVIIa-induced signaling. Activation of the p44/42 MAPK pathway upon binding of FVIIa to TF was demonstrated by suppression of signaling with the specific kinase inhibitor PD98059 and demonstration of a transient p44/42 MAPK phosphorylation. No stimulation of p44/42 MAPK phosphorylation was observed with catalytically inactive FVIIa derivatives suggesting that the catalytic activity of FVIIa was obligatory for activation of the MAPK pathway. Signal transduction caused by a putative generation of FXa activity was excluded by experiments showing that FVIIa/TF-induced signaling was not quenched by tick anticoagulant protein, just as addition of FXa could not induce phosphorylation of p44/42 MAPK in BHK(+TF) cells. These results suggest a specific mechanism by which binding of FVIIa to cell surface TF independent of coagulation can modulate cellular functions and possibly play a role in angiogenesis and tumor metastasis as indicated by several recent observations.

In the majority of patients with systemic inflammatory conditions, some degree of activation of coagulation is present. Increasing evidence points to an extensive cross-talk between coagulation and inflammation that may play an important role in vascular obstruction and organ dysfunction that is associated with severe inflammation. Inflammation not only leads to activation of coagulation but also considerably affects inflammatory activity. Molecular pathways that contribute to inflammation-induced activation of coagulation have been precisely identified. Proinflammatory cytokines and other mediators are capable of activating the coagulation system and downregulating important physiological anticoagulant pathways. Activation of the coagulation system and ensuing thrombin generation is dependent on expression of tissue factor on activated mononuclear cells and endothelial cells and is insufficiently counteracted by tissue factor pathway inhibitor. Simultaneously, endothelial-bound anticoagulant mechanisms, in particular the protein C system, is shut off by proinflammatory cytokines. In addition, fibrin removal is severely inhibited due to inactivation of the fibrinolytic system, caused by an upregulation of its main inhibitor, plasminogen activator inhibitor type 1 (PAI-1). The cornerstone of the management of inflammation-associated coagulation is the specific and vigorous treatment of the underlying disorder. Strategies aimed at the inhibition of coagulation activation may theoretically be justified and have been found beneficial in experimental and initial clinical studies. Heparin may be an effective anticoagulant approach and alternative strategies comprise restoration of physiological anticoagulant pathways.