Thromboembolism is the second leading cause of death among patients with non-small cell lung cancer (NSCLC), but the precise mechanisms of thrombogenesis in NSCLC remain largely unknown. Our objectives were to evaluate the definitive role of neutrophil extracellular traps (NETs) in the hypercoagulability in NSCLC and to explore its interactions with platelets and endothelial cells (ECs).

 The levels of NET markers in samples from 100 NSCLC patients and 30 healthy controls were measured by ELISA. NET formation was detected using immunofluorescence. Procoagulant activity was assessed based on purified coagulation complex, thrombin, clotting time, and fibrin formation assays.

 The plasma levels of NETs were increased in a stage-dependent manner in NSCLC patients and were markedly higher than those in controls. Neutrophils from NSCLC patients were more prone to form NETs, resulting in shortened coagulation time, significantly increased thrombin-antithrombin complexes and fibrin compared to controls. Moreover, NETs generation was mediated by High Mobility Group Box 1 from activated platelets in NSCLC patients. Conversely, NETs from NSCLC patients also induce phosphatidylserine exposure on platelets, leading to markedly enhanced procoagulant activity (PCA). Furthermore, NETs can damage endothelial cells and convert them to a procoagulant phenotype. The administration of NETs inhibitors (DNase I/activated protein C) could markedly diminish the PCA of NETs, activated platelets, and ECs.

 Our results suggest that NETs contribute to hypercoagulability and may represent a potential therapeutic target to prevent cancer-associated thrombosis in NSCLC patients.

A hypoxic tumor microenvironment inhibits the normal functioning of immune cells. Studies have hypothesized that anticoagulants that can penetrate and bind to factor Xa in the tumor microenvironment, can enhance T-cell function and augment immunotherapy activity. This study compared objective response rate and progression-free survival of lung cancer patients on concomitant immunotherapy treated with direct-acting oral anticoagulants versus enoxaparin.

This single-center retrospective study included 73 adults with stage-IV lung cancer who received at least two cycles of immunotherapy and one month of anticoagulant therapy with direct-acting oral anticoagulants (Arm A) versus enoxaparin (Arm B) between June 1, 2016, to September 30, 2022. Primary endpoint was objective response rate, and secondary endpoints were rates of complete response, progression-free survival, incidence of thrombotic events, and major bleeding.

Objective response rate at 6 months was 24.5% versus 25% while progression-free survival at 6 months was 54.7% versus 45% in Arm A versus Arm B, respectively. Complete response rates at 6 months were 7.5% in Arm A versus 0% in Arm B. One patient in Arm A and two in Arm B had a recurrent deep vein thrombosis. Nine patients in Arm A and two in Arm B were diagnosed with new deep vein thrombosis. One patient in Arm B was diagnosed with new pulmonary embolism. Two major bleeding events occurred in Arm B.

Our study suggests a trend toward improved progression-free survival at 6 months with no new safety concerns in lung cancer patients on concurrent immunotherapy and direct-acting oral anticoagulants.

Relationships between low socioeconomic status and surgical outcomes are well established for certain procedures. However, scant literature has focused on relationships between median household income and lumbar fusion outcomes.

Patients who underwent fusion procedures between January 1, 2009 and December 31, 2020 were identified from the National Inpatient Sample database. They were categorized into 4 quartiles, from lowest to highest, based on median household incomes in respective zip codes. We applied univariable and multivariable linear and logistic regression models to analyze perioperative data according to income quartiles.

We included 2,826,396 patients. In multivariable regression, patients in the 3 lowest income quartiles exhibited higher rates of in-hospital cardiac events perioperatively, with odds ratios (ORs) of 1.19 (95% confidence interval [CI]1.13-1.26, P < 0.001), 1.10 (95% CI 1.05-1.16, P < 0.001), and 1.06 (95% CI 1.01-1.12, P = 0.011) for the first, second, and third quartiles, respectively. Patients in the lowest income (first) quartile had a higher occurrence of perioperative urinary complications (OR = 1.07, 95% CI 1.03-1.12, P = 0.001), systemic infectious complications (OR = 1.17, 95% CI 1.04-1.32, P = 0.006), neurological deficit (OR = 1.17, 95% CI 1.06-1.30, P = 0.002), and wound infections (OR = 1.22, 95% CI 1.12-1.34, P < 0.001). Those in the 3 lowest income quartiles were less likely to experience respiratory, gastrointestinal, and venous thrombotic complications (P < 0.05). The lowest income quartile had protective associations for dural tears (OR 0.93, 95% CI 0.89-0.99, P = 0.038) and postprocedure anemia across all 3 lower quartiles, with OR < 1 and P < 0.001.

Reduced household income significantly affected perioperative outcomes after lumbar fusion and should be taken into consideration during the perioperative period.

To investigate the inhibitory effect of Celastrus orbiculatus extracts (COE) on the proliferation of lymphoma cells and the immune regulation ability on inflammation and thrombophilia in vivo.

The 38B9 lymphoma cells were treated with COE (160 µ g/mL) and CTX (25 µ mol/L). The apoptosis rate and cell cycle of each group were detected by flow cytometry. The secretion of inflammatory factors, including interleukin (IL)-6, IL-10, and tumor necrosis factor α (TNF-α), in cell supernatant was detected by enzyme-linked immunosorbent assay (ELISA). In vivo, BALB/c mice were subcutaneously injected with 38B9 lymphoma cells to establish lymphoma model. COE (3 mg·kg-1·d-1) and CTX (40 mg·kg-1·d-1) were administered to the model mice, respectively. The expression of plasma inflammatory factors (IL-6, IL-10 and TNF-α) and thrombus indexes, including D-dimer (D-D), von Willebrand factor (vWF) and tissue factor (TF), were detected by ELISA before tumor bearing (1 d), after tumor formation (14 d) and after intervention (21 d). PicoGreen dsDNA was used to detect the level of serum neutrophil extracellular traps (NETs). Flow cytometry was used to detect the expression of platelet activation marker calcium-dependent lectin-like receptor 2 (CLEC-2). The tumor growth and survival of mice were recorded.

The 38B9 lymphoma cells were apoptotic after the intervention of COE and CTX. The ratio of G2-M phase cells decreased in COE intervented cells compared with the control cells (P<0.05), and S phase cells decreased in CTX intervented cells (P<0.05). Also, the secretion level of IL-6 was significantly reduced after COE or CTX intervention (P<0.05), and IL-10 was significantly increased (P<0.05). Furthermore, the tumor mass was reduced, and the median survival time was longer in COE and CTX intervented tumor-bearing mice than in non-intervented mice. The significantly lower levels of TNF-α, IL-6, NETs, TF, DD and CLEC-2, as well as higher IL-10 were observed in COE and CTX treatment mice in comparision with the control mice (P<0.05).

COE has a mild and stable anti-tumor effect, which can reduce the secretion of inflammatory factors by lymphoma cells and regulate thrombophilic state caused by tumor inflammatory microenvironment.

 Real-world data on clinical characteristics and outcomes related to the use of different direct oral anticoagulants (DOACs) for cancer-associated venous thromboembolism (VTE) is lacking.

 The COMMAND VTE Registry-2 is a multicenter registry enrolling 5,197 consecutive patients with acute symptomatic VTE from 31 centers in Japan from January 2015 to August 2020. Our study population comprised 1,197 patients with active cancer who were divided into the edoxaban (N = 643, 54%), rivaroxaban (N = 297, 25%), and apixaban (N = 257, 22%) groups.

 The cumulative 5-year incidence of recurrent VTE (9.3, 10.2, and 8.5%, respectively, p = 0.82) and all-cause death (67.5, 66.8, and 63.8%, respectively, p = 0.22) did not differ among the groups. Despite adjusting for confounders, the risks of recurrent VTE and all-cause death did not differ significantly among the groups. The cumulative 5-year incidence of major and clinically relevant bleeding was significantly lower in the rivaroxaban group than those in the other groups (22.6, 14.0, and 22.8%, p = 0.04; and 37.6, 26.8, and 38.3%, p = 0.01, respectively). After adjusting for confounders, in the rivaroxaban group, the risk for major bleeding was numerically lower (hazard ratio [HR]: 0.65, 95% confidence interval [CI]: 0.40-1.01) and that of clinically relevant all bleeding was significantly lower (HR: 0.67, 95% CI: 0.48-0.92) than those in the edoxaban group.

 The risks of recurrent VTE and all-cause death did not differ significantly among the different DOACs ; however, the risk of bleeding events could differ, with a potentially lower risk of bleeding with rivaroxaban.

Introduction  Gastrointestinal (GI) malignancies represent a diverse group of cancers affecting various parts of the digestive system. These malignancies encompass an important burden of cancer incidence and mortality globally, contributing to substantial morbidity and mortality worldwide. Studying the coagulation parameters of patients having GI malignancies is crucial for several reasons. It allows to identify the patients at an increased risk of thrombotic complications, enabling clinicians to implement appropriate prophylactic measures, such as anticoagulant therapy or mechanical thromboprophylaxis. Aim  To study coagulation parameters in patients diagnosed with GI malignancies. Materials and methods The present study is a two-year prospective observational study, carried out in the Department of Pathology in our tertiary care institute from July 2022 to June 2024 to investigate the coagulation profile in patients diagnosed with GI malignancies. A total of 86 cases were studied. Results  A significant increase in the mean values of coagulation parameters was noted with an increase in the grade of malignancy. Conclusion  Early examination for the presence of coagulation abnormalities can help to prevent morbidity and mortality and other bleeding diathesis in GI malignancies as alterations in the coagulation pathway can lead to lethal complications.

Venous thromboembolism, which is common in cancer patients and accompanies or even precedes malignant tumors, is known as cancer-related thrombosis and is an important cause of cancer- associated death. At present, the exact etiology of the elevated incidence of venous thrombosis in cancer patients remains elusive. Platelets play a crucial role in blood coagulation, which is intimately linked to the development of arterial thrombosis. Additionally, platelets contribute to tumor progression and facilitate immune evasion by tumors. Tumor cells can interact with the coagulation system through various mechanisms, such as producing hemostatic proteins, activating platelets, and directly adhering to normal cells. The relationship between platelets and malignant tumors is also significant. In this review article, we will explore these connections.

Treating cancer-associated venous thromboembolism (CAT) with anticoagulation prevents recurrent venous thromboembolism (rVTE), but increases bleeding risk.

To compare incidence of rVTE, major bleeding, and all-cause mortality for rivaroxaban versus low molecular weight heparin (LMWH) in patients with CAT.

We developed a cohort study using Swedish national registers 2013-2019. Patients with CAT (venous thromboembolism within 6 months of cancer diagnosis) were included. Those with other indications or with high bleeding risk cancers were excluded (according to guidelines). Follow-up was from index-CAT until outcome, death, emigration, or end of study. Incidence rates (IR) per 1000 person-years with 95% confidence interval (CI) and propensity score overlap-weighted hazard ratios (HRs) for rivaroxaban versus LMWH were estimated.

We included 283 patients on rivaroxaban and 5181 on LMWH. The IR for rVTE was 68.7 (95% CI 40.0-109.9) for rivaroxaban, compared with 91.6 (95% CI 81.9-102.0) for LMWH, with adjusted HR 0.77 (95% CI 0.43-1.35). The IR for major bleeding was 23.5 (95% CI 8.6-51.1) for rivaroxaban versus 49.2 (95% CI 42.3-56.9) for LMWH, with adjusted HR 0.62 (95% CI 0.26-1.49). The IR for all-cause mortality was 146.8 (95% CI 103.9-201.5) for rivaroxaban and 565.6 (95% CI 541.8-590.2) for LMWH with adjusted HR 0.48 (95% CI 0.34-0.67).

Rivaroxaban performed similarly to LMWH for patients with CAT for rVTE and major bleeding. An all-cause mortality benefit was observed for rivaroxaban which potentially may be attributed to residual confounding.

NCT05150938 (Registered 9 December 2021).

Prostate cancer is the most common cancer diagnosed in men and the second leading cause of death in male cancer patients. The WHO suggests that cobalt is involved in the carcinogenesis of prostate cancer. There are, however, no studies associating cobalt levels and prostate cancer patient survival. In this study, 261 Polish prostate cancer (n = 261) patients were recruited into a prospective cohort between 2009 and 2015. Serum cobalt levels were measured using ICP-MS after prostate cancer diagnosis and before treatment. All study participants were assigned into quartiles (QI-QIV) based on the distribution of serum cobalt levels among censored patients. Univariable and multivariable COX regression models were used to calculate hazard ratios (HRs) for each serum cobalt level quartile. We found a significant relationship between high serum cobalt levels and poor prostate cancer patient total survival (HR = 2.60; 95% CI: 1.17-5.82; p = 0.02). In relation to prostate cancer patients who died as a result of other non-cancer causes, the association with high levels of cobalt was even stronger (HR = 3.67; 95% CI: 1.03-13.00; p = 0.04). The impact of high serum cobalt levels on overall survival of prostate cancer-specific-related deaths was not statistically significant.

Objective Edoxaban is an anticoagulant used for venous thromboembolism (VTE) treatment and requires pretreatment with parenteral anticoagulants. However, pretreatment is not always performed in the clinical setting. In this study, we investigated the safety and effectiveness of edoxaban treatment in patients with VTE with or without pretreatment. Methods We retrospectively enrolled 364 patients who received edoxaban for VTE treatment between September 2014 and March 2020 and investigated patient demographics, VTE recurrence, and major bleeding as clinical outcomes in patients with or without pretreatment. Furthermore, the factors contributing to pretreatment decisions were assessed. Results Patients without pretreatment (n=208) had more active cancer cases and fewer pulmonary embolism complications than those with pretreatment (n=156). Lower levels of hemoglobin and higher levels of white blood cell counts, C-reactive protein, and D-dimer at the diagnosis were found in patients who received pretreatment than in those without pretreatment. No symptomatic VTE recurrence was observed. After propensity score matching, the cumulative incidence of major bleeding was not significantly higher in patients with pretreatment than in those without it (log-rank test, p=0.136). The incidence of deteriorated VTE on imaging did not significantly differ between patients with and without pretreatment, even after propensity matching (log-rank test, p=0.414). Conclusion In a real-world clinical setting, where physicians determined the use of parenteral anticoagulant lead-in according to their experience, patient demographics, and VTE characteristics, no significant differences were found regarding safety and effectiveness in edoxaban-treated VTE patients with or without pretreatment with parenteral anticoagulants.

Cancer-associated thrombosis (CAT) has been identified as the second most prevalent cause of death after cancer itself. Moreover, the risk of thrombotic events in cancer patients increases due to anticancer drugs, such as tyrosine kinase inhibitors (TKIs). Venous thromboembolism (VTE) as well as arterial thromboembolic (ATE) events are present in CAT. Although VTE occurs more frequently, ATE events are very significant and in some cases are more dangerous than VTE. Guidelines for preventing thrombosis refer mainly VTE as well as the contribution of ATE events. Several factors are involved in thrombosis related to cancer, but the whole pathomechanism of thrombosis is not clear and may differ between patients. The activation of the coagulation system and the interaction of cancer cells with other cells including platelets, endothelial cells, monocytes, and neutrophils are promoted by a hypercoagulable state caused by cancer. We present an update on the pathomechanisms of CAT and the effect of anticancer drugs, mainly targeted therapies with a focus on TKIs. Considering the risk of bleeding associated with anticoagulation in each cancer patient, the anticoagulation strategy may involve the use of FXIa inhibitors, direct oral anticoagulants, and low-molecular-weight heparin. Further research would be valuable in developing strategies for reducing CAT.

Pancreatic ductal adenocarcinoma (PDAC) accounts for more than 90% of all pancreatic cancers and is the most fatal of all cancers. The treatment response from combination chemotherapies is far from satisfactory and surgery remains the mainstay of curative strategies. These challenges warrant identifying effective treatments for combating this deadly cancer. PDAC tumor progression is associated with the robust activation of the coagulation system. Notably, cancer-associated thrombosis (CAT) is a significant risk factor in PDAC. CAT is a concept whereby cancer cells promote thromboembolism, primarily venous thromboembolism (VTE). Of all cancer types, PDAC is associated with the highest risk of developing VTE. Hypoxia in a PDAC tumor microenvironment also elevates thrombotic risk. Direct oral anticoagulants (DOACs) or low-molecular-weight heparin (LMWH) are used only as thromboprophylaxis in PDAC. However, a precision medicine approach is recommended to determine the precise dose and duration of thromboprophylaxis in clinical setting.

Thrombosis and bleeding are commonly observed in cancer patients, and their management is crucial for positive patient outcomes. A comprehensive, prophylactic, and therapeutic management of venous thrombosis should focus on identifying the patients who would benefit most from treatment to reduce mortality and minimize the risk of thrombosis recurrence without significantly increasing the risk of bleeding. Existing cancer scales provide valuable information for assessing the overall burden of cancer and guiding treatment decisions, but their ability to predict thrombotic and bleeding events remains limited. With increasing knowledge of the pathophysiology of cancer and the availability of advanced anticancer therapies, new risk factors for cancer-associated thrombosis and bleeding are being identified. In this report, we analyze the current literature and identify new risk factors for venous thrombosis and bleeding which are not included in routinely used risk scores. While some existing cancer scales partially capture the risk of thrombosis and bleeding, there is a need for more specific and accurate scales tailored to these complications. The development of such scales could improve risk stratification, aid in treatment selection, and enhance patient care. Therefore, further research and development of novel cancer scales focused on thrombosis and bleeding are warranted to optimize patient management and outcomes.

Currently, minimal data are available to explore the composition of venous thromboembolism in patients with cancer. This case report discusses a presentation of venous thromboembolism in a patient with high-grade urothelial carcinoma and highlights the pathology findings in thrombi. Case Presentation. A 55-year-old female who was diagnosed with high-grade urothelial carcinoma with multiple metastases developed an extensive deep vein thrombosis in her left lower extremity. Endovascular revascularization was indicated due to left lower extremity pain and swelling not responsive to anticoagulation. A mechanical thrombectomy was performed, and samples were sent for pathology. Pathologic examination discovered minute fragments of metastatic carcinoma, admixed with laminated blood clots (thrombus). The morphology of metastatic carcinoma and the immunostain profile were compatible with metastatic carcinoma of bladder origin.

Cancer is a well-known risk factor for developing VTEs, and it is estimated that approximately 4-20% of cancer patients will experience VTE at some stage, the rate being the highest in the initial period following diagnosis. Annually, 0.5% of cancer patients will experience thrombosis compared with a 0.1% incidence rate in the general population (Elyamany et al., 2014). Despite knowing the increased incidence of VTEs in cancer patients, there are few studies to date that analyze the composition of thrombi in patients with cancer.

Cancer-associated thrombosis (CAT) and venous thromboembolism (VTE) are frequent cancer-related complications associated with high mortality; thus, this urges the identification of predictive markers. Immune checkpoint inhibitors (ICIs) used in cancer immunotherapy allow T-cell activation against cancer cells. Retrospective studies showed increased VTE following ICI administration in some patients. Non-small cell lung cancer (NSCLC) patients are at high risk of thrombosis and thus, the adoption of immunotherapy, as a first-line treatment, seems to be associated with coagulation-fibrinolysis derangement.

We pharmacologically modulated NSCLC cell lines in co-culture with CD8+ T-cells (TCD8+) and myeloid-derived suppressor cells (MDSCs), isolated from healthy blood donors. The effects of ICIs Nivolumab and Ipilimumab on NSCLC cell death were assessed by annexin V and propidium iodide (PI) flow cytometry analysis. The potential procoagulant properties were analyzed by in vitro clotting assays and enzyme-linked immunosorbent assays (ELISAs). The metabolic remodeling induced by the ICIs was explored by 1H nuclear magnetic resonance (NMR) spectroscopy.

Flow cytometry analysis showed that TCD8+ and ICIs increase cell death in H292 and PC-9 cells but not in A549 cells. Conditioned media from NSCLC cells exposed to TCD8+ and ICI induced in vitro platelet aggregation. In A549, Podoplanin (PDPN) levels increased with Nivolumab. In H292, ICIs increased PDPN levels in the absence of TCD8+. In PC-9, Ipilimumab decreased PDPN levels, this effect being rescued by TCD8+. MDSCs did not interfere with the effect of TCD8+ in the production of TF or PDPN in any NSCLC cell lines. The exometabolome showed a metabolic remodeling in NSCLC cells upon exposure to TCD8+ and ICIs.

This study provides some insights into the interplay of immune cells, ICIs and cancer cells influencing the coagulation status. ICIs are important promoters of coagulation, benefiting from TCD8+ mediation. The exometabolome analysis highlighted the relevance of acetate, pyruvate, glycine, glutamine, valine, leucine and isoleucine as biomarkers. Further investigation is needed to validate this finding in a cohort of NSCLC patients.

Phlegmasia cerulea dolens (PCD) is a rare yet severe complication of deep vein thrombosis (DVT), characterized by a high amputation rate and mortality. Early diagnosis and treatment are crucial in managing this condition. PCD predominantly affects the lower extremities rather than the upper extremities. We herein present a rare upper extremity PCD case accompanied with supra vena cava and pulmonary embolism in a cervical cancer patient, who presented to our institution with severe pain, edema and irreversible venous gangrene of right upper limb with no response to anticoagulation therapy. Emergency fasciotomy and amputation were performed due to the progressed venous gangrene, however, the patient developed severe infection and coagulation disorders, gastrointestinal bleeding and disseminated intravascular coagulation after the surgery. Despite medical interventions, her family chose to withdraw treatment and the patient died in ICU at the fourth day following emergency surgery.

Despite the occurrence of various hemorrhagic events during advanced lung cancer treatment, few researchers have reported on their risk factors. Moreover, the development of cancer-related thromboembolism indicates anticoagulant use. However, adverse events such as bleeding should be monitored. In this study, we aimed to identify factors that influence the onset of hemorrhagic events in patients with lung cancer. The Rising-VTE/NEJ037 study was a multicenter, prospective, observational study. A total of 1008 patients with lung cancer who were unsuitable for radical resection or radiation were enrolled and followed up for 2 years. Multivariate analysis using a Cox proportional hazard model was performed to compare the outcomes of the time to the onset of hemorrhagic events for 2 years after registration. Hemorrhagic events occurred in 115 patients (11.4%), with 35 (30.4%) experiencing major bleeding. Significant risk factors included venous thromboembolism (VTE) (hazard ratio [HR]: 4.003, p < 0.001) and an Eastern Cooperative Oncology Group Performance Status score of 1 (HR: 2.476, p < 0.001). Factors that significantly reduced hemorrhagic event risk were female sex (HR: 0.454, p = 0.002) and M1a status (HR: 0.542, p = 0.038). VTE is a risk factor for hemorrhagic events in patients with advanced lung cancer, and risks associated with anticoagulant therapy should be considered.

Background  Although the close relationship between cancer and venous thromboembolism (VTE) has been identified, risk stratification for VTE in Japanese patients with cancer remains unclear. Objectives  This study aimed to validate the Khorana VTE risk assessment score (KRS) for VTE diagnosis and establish an optimal predictive model for VTE in Japanese patients with cancer. Methods  A total of 7,955 Japanese patients with cancer were subdivided into low- (0), intermediate- (1-2), and high-score (3) groups according to the KRS. Using 37 explanatory variables, a total of 2,833 patients with cancer were divided into derivation and validation cohorts (5:5). A risk model for Japanese participants was developed using the derivation cohort data. Results  The prevalence of VTE in low-, intermediate-, and high-score patients was 1.2, 2.5, and 4.3%, respectively. Logistic regression analysis demonstrated that cancer stage (III-IV) and KRS ≥ 2 were independent and significant predictors of VTE onset. The risk model for VTE assigned 1 point to body mass index ≥25 kg/m 2 and 2 points each to the prevalence of osteochondral cancer and D-dimer level ≥1.47 µg/mL. The areas under the curve of the risk model were 0.763 and 0.656 in the derivation and validation cohorts, respectively. Conclusion  The KRS was useful in Japanese patients, and our new predictive model may be helpful for the diagnosis of VTE in Japanese patients with cancer.

A 48-year-old woman with advanced ovarian cancer was diagnosed with pulmonary tumor thrombotic microangiopathy (PTTM) by antemortem pulmonary wedge aspiration cytopathology. Despite the initiation of anti-cancer treatment, she unfortunately died due to progressive respiratory failure. Histopathology of the autopsied lung revealed multiple tumor embolization with fibrin-rich clot and fibro-cellular intimal proliferation at the pulmonary arteriole. The embolized tumor showed strong immune-positivity for pro-thrombotic and fibrotic factors (tissue factor and vascular endothelial growth factor), suggesting the underlying mechanisms of PTTM development. This case suggests that a quick antemortem diagnosis and the early induction of specific treatments might ensure a better prognosis of PTTM.

Cancer-associated thrombosis (CAT) is one of the major complications during the treatment course of cancer, which often challenges clinicians in daily clinical practice despite anticoagulation therapy.

A 57-year-old man with a history of a liver transplantation was diagnosed with post-transplant lymphoproliferative disorders. He developed severe systemic thromboses including a massive pulmonary embolism and was treated with anticoagulation therapy including a factor Xa inhibitor. However, the systemic thromboses worsened despite the anticoagulation therapy. During the acute treatment course of the thromboses, we administered anticancer drug therapy in hopes of an improvement in the activity of the cancer status leading to a favourable effect on the thrombosis status. Multi-disciplinary treatment including anticoagulation therapy and anticancer drug therapy successfully improved the systemic thrombosis.

Anticoagulation therapy is a standard treatment for CAT; however, some cases of CAT do not successfully improve despite anticoagulation therapy, partly due to a highly active cancer status. Anticancer drug therapy might increase the risk of a thrombosis, whereas it could improve the activity of the cancer status leading to a decreased risk of a thrombosis. A multi-disciplinary therapy might be a reasonable option especially for CAT with a highly active cancer status.

Tranexamic acid (TXA) is an antifibrinolytic drug that has been shown to reduce blood loss following surgery. The use of TXA during orthopedic procedures has gained widespread acceptance, with multiple clinical studies demonstrating no increase in thrombotic complications. While TXA has been shown to be safe and effective for several orthopedic procedures, its use in orthopedic sarcoma surgery is not well established. Cancer-associated thrombosis remains a significant cause of morbidity and mortality in patients with sarcoma. It is unknown if intraoperative TXA use will increase the risk of developing a postoperative thrombotic complication in this population. This study aimed to compare the risk of postoperative thrombotic complications in patients who received TXA during sarcoma resection to patients who did not receive TXA.

A retrospective review was performed of 1099 patients who underwent resection of a soft tissue or bone sarcoma at our institution between 2010 and 2021. Baseline demographics and postoperative outcomes were compared between patients who did and did not receive intraoperative TXA. We evaluated 90-day complication rates, including: deep venous thrombosis (DVT), pulmonary embolism (PE), myocardial infarction (MI), cerebrovascular accident (CVA), and mortality.

TXA was used more commonly for bone tumors (p < 0.001), tumors located in the pelvis (p = 0.004), and larger tumors (p < 0.001). Patients who received intraoperative TXA were associated with a significant increase in developing a postoperative DVT (odds ratio [OR]: 2.22, p = 0.036) and PE (OR: 4.62, p < 0.001), but had no increase in CVA, MI, or mortality (all p > 0.05) within 90 days of surgery, following univariate analysis. Multivariable analysis confirmed that TXA was independently associated with developing a postoperative PE (OR: 10.64, 95% confidence interval: 2.23-50.86, p = 0.003). We found no association with DVT, MI, CVA, or mortality within 90 days postoperatively, following intraoperative TXA use.

Our results demonstrate a higher associated risk of PE following TXA use in sarcoma surgery and caution is warranted with TXA use in this patient population.

Thrombosis is a common complication of advanced cancer, yet the cellular mechanisms linking malignancy to thrombosis are poorly understood. The unfolded protein response (UPR) is an ER stress response associated with advanced cancers. A proteomic evaluation of plasma from patients with gastric and non-small cell lung cancer who were monitored prospectively for venous thromboembolism demonstrated increased levels of UPR-related markers in plasma of patients who developed clots compared with those who did not. Release of procoagulant activity into supernatants of gastric, lung, and pancreatic cancer cells was enhanced by UPR induction and blocked by antagonists of the UPR receptors inositol-requiring enzyme 1α (IRE1α) and protein kinase RNA-like endoplasmic reticulum kinase (PERK). Release of extracellular vesicles bearing tissue factor (EVTFs) from pancreatic cancer cells was inhibited by siRNA-mediated knockdown of IRE1α/XBP1 or PERK pathways. Induction of UPR did not increase tissue factor (TF) synthesis, but rather stimulated localization of TF to the cell surface. UPR-induced TF delivery to EVTFs was inhibited by ADP-ribosylation factor 1 knockdown or GBF1 antagonism, verifying the role of vesicular trafficking. Our findings show that UPR activation resulted in increased vesicular trafficking leading to release of prothrombotic EVTFs, thus providing a mechanistic link between ER stress and cancer-associated thrombosis.

Factors related to coagulation regulation are closely related to angiogenesis, epithelial-mesenchymal transition, tumor proliferation and metastasis, and tumor immune microenvironment remodeling in tumors. To date, there are no quantitative indicators of coagulation associated with urothelial cancer. We classified urothelial cancer into high coagulation and low coagulation subtypes by screening for procoagulant-related molecular features and screened out relevant genes representing the coagulation state of urothelial carcinoma. Tumors with increased procoagulant gene expression were consistently associated with higher T-staging (p < 0.001), lymph node metastasis (p < 0.001), stage (p < 0.001), and grade (p = 0.046). Furthermore, high expression of procoagulant genes predicts a worse prognosis, a higher tumor proliferation rate and increased angiogenesis within the tumor. In addition, according to cibersort algorithm, the increased expression of procoagulant gene was negatively correlated with the degree of T-lymphocyte infiltration and positively correlated with the degree of M2 macrophage infiltration. Increased expression of procoagulant genes in data sets treated with immune checkpoints also predicted worse response and worse prognosis. At the same time, the expression of procoagulant genes in bladder cancer promoted the activation of coagulation, EMT, TGF-β and WNT pathways.

A bidirectional association exists between metastatic dissemination and the hypercoagulable state associated with many types of cancer. As such, clinical studies have provided evidence that markers associated with elevated levels of coagulation and fibrinolysis correlate with decreased patient survival. However, elucidating the mechanisms underpinning the effects of different components of the coagulation system on metastasis formation is challenging both in animal models and 2D models lacking the complex cellular interactions necessary to model both thrombosis and metastasis. Here, an in vitro, 3D, microvascular model for observing the formation of fibrin thrombi is described, which is in turn used to study how different aspects of the hypercoagulable state associated with cancer affect the endothelium. Using this platform, cancer cells expressing ICAM-1 are shown to form a fibrinogen-dependent bridge and transmigrate through the endothelium more effectively. Cancer cells are also demonstrated to interact with fibrin thrombi, using them to adhere, spread, and enhance their extravasation efficiency. Finally, thrombin is also shown to enhance cancer cell extravasation. This system presents a physiologically relevant model of fibrin clot formation in the human microvasculature, enabling in-depth investigation of the cellular interactions between cancer cells and the coagulation system affecting cancer cell extravasation.

In the era of the SARS-Cov2 pandemic, the multidisciplinary care of patients with lung cancer is the main challenge for clinicians. The depiction of complex networking between SARS-CoV2 and cancer cells is crucial to understanding the downstream signalling pathways leading to more severe clinical behaviour of COVID-19 among lung cancer patients.

The immunosuppressive status caused by both blunted immune response and active anticancer treatments (e.g. radiotherapy, chemotherapy) affects also the response to vaccines. Furthermore, the COVID-19 pandemic has significantly influenced early detection, therapeutic management, and clinical research for patients with lung cancer.

SARS-CoV-2 infection does undoubtedly represent a challenge for care of patients with lung cancer. Since symptoms of infection may overlap with underlying condition, diagnosis must be reached and treatment should start as soon as possible. Although any cancer treatment should be procrastinated as long as infection is not cured, every choice must be pondered on individual basis, according to clinical conditions. Underdiagnosis should be avoided, and both surgical and medical treatment must be tailored to each patient. Therapeutic scenario standardization represents a major challenge for clinicians and researchers.

Identifying changes in epidemiologic patterns of the incidence and risk of cancer-associated thrombosis (CAT), particularly with evolving cancer-directed therapy, is essential for risk stratification.

To assess the incidence of CAT over time and to determine pertinent patient-specific, cancer-specific, and treatment-specific factors associated with its risk.

This longitudinal, retrospective cohort study was conducted from 2006 to 2021. Duration of follow-up was from the date of diagnosis until first venous thromboembolism (VTE) event, death, loss of follow-up (defined as a 90-day gap without clinical encounters), or administrative censoring on April 1, 2022. The study took place within the US Department of Veterans Affairs national health care system. Patients with newly diagnosed invasive solid tumors and hematologic neoplasms were included in the study. Data were analyzed from December 2022 to February 2023.

Newly diagnosed invasive solid tumors and hematologic neoplasms.

Incidence of VTE was assessed using a combination of International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification and natural language processing confirmed outcomes. Cumulative incidence competing risk functions were used to estimate incidence of CAT. Multivariable Cox regression models were built to assess the association of baseline variables with CAT. Pertinent patient variables included demographics, region, rurality, area deprivation index, National Cancer Institute comorbidity index, cancer type, staging, first-line systemic treatment within 3 months (time-varying covariate), and other factors that could be associated with the risk of VTE.

A total of 434 203 patients (420 244 men [96.8%]; median [IQR] age, 67 [62-74] years; 7414 Asian or Pacific Islander patients [1.7%]; 20 193 Hispanic patients [4.7%]; 89 371 non-Hispanic Black patients [20.6%]; 313 157 non-Hispanic White patients [72.1%]) met the inclusion criteria. Overall incidence of CAT at 12 months was 4.5%, with yearly trends ranging stably from 4.2% to 4.7%. The risk of VTE was associated with cancer type and stage. In addition to confirming well-known risk distribution among patients with solid tumors, a higher risk of VTE was observed among patients with aggressive lymphoid neoplasms compared with patients with indolent lymphoid or myeloid hematologic neoplasms. Compared with no treatment, patients receiving first-line chemotherapy (hazard ratio [HR], 1.44; 95% CI, 1.40-1.49) and immune checkpoint inhibitors (HR, 1.49; 95% CI, 1.22-1.82) had a higher adjusted relative risk than patients receiving targeted therapy (HR, 1.21; 95% CI, 1.13-1.30) or endocrine therapy (HR, 1.20; 95% CI, 1.12-1.28). Finally, adjusted VTE risk was significantly higher among Non-Hispanic Black patients (HR, 1.23; 95% CI, 1.19-1.27) and significantly lower in Asian or Pacific Islander patients (HR, 0.84; 95% CI, 0.76-0.93) compared with Non-Hispanic White patients.

In this cohort study of patients with cancer, a high incidence of VTE was observed, with yearly trends that remained stable over the 16-year study period. Both novel and known factors associated with the risk of CAT were identified, providing valuable and applicable insights in this current treatment landscape.

Neoplasmatic disease increases the risk of acute pulmonary embolism (APE) by different pathophysiological mechanisms that favor thrombosis in patients with cancer. Recently, the role of cancer (active and occult) in the prevalence of venous thromboembolism has been discussed more thoroughly in the subject literature.

Medical records of 366 consecutive patients with a diagnosis of APE (aged: mean = 65.0 ± 16.6, median = 68, range = 19-94; men = 41%/women = 59%) were collected with a wide range of demographic data, medical history of coexisting diseases, computer examination, and laboratory tests.

The APE patients were analyzed in two groups: negative cancer cases (83%), i.e. without concomitant active malignancy or a history of cancer, and positive ones (17%), i.e. those hospitalized with concomitant active cancer disease or a history of cancer within the past 5 years.

Based on the application of the Student's t-test for independent samples and the χ2 test of independence, a statistically significant difference (P < 0.05) between cancer (-) and cancer(+) groups of patients was calculated for the following selected risk factors: BMI, smoking status, hemoglobin, hematocrit, red blood cell, urea, glomerular filtration rate, high-sensitivity troponin T, C-reactive protein (CRP), D-dimer, and NT-proBNP. Using univariate Cox regression and a discrete-time hazard model, the estimated hazard ratios and odds ratios, respectively, for the risk of an earlier death from cancer as well as for a secondary APE episode in APE patients with malignancy are more than three times higher than in cancer-free patients and they are statistically significant (P < 0.05). Moreover, the modeled discrete-time hazard curves show a constant excess risk of death and a secondary APE episode in patients diagnosed with malignancy over the period of observation.

Cancer and APE seem to go 'hand in hand'. Attention should be paid to many factors, primarily clinical, differentiating patients with cancer from those with an APE incident. The patients with cancer after a primary APE should receive anticoagulants to prevent a secondary APE episode and to reduce the risk of mortality.

Deep vein thrombosis (DVT) is a common complication in cancer. Although thromboprophylaxis in cancer patients is recommended by the guidelines, clinicians' use of thromboprophylaxis remains limited due to cost, bleeding complications, and reluctance to give injectable anticoagulants. Inflammation plays essential roles in the pathogenesis of cancer-associated thrombosis. Owing to its ability to decrease proinflammatory cytokines, statins have anti-inflammatory properties. Thus, statins can be possibly utilized as thromboprophylaxis therapy in cancer patients undergoing chemotherapy.

To compare the effectiveness of atorvastatin and rivaroxaban for DVT prevention in high-risk thrombosis patients with cancer undergoing chemotherapy.

Double-blind, randomized controlled trial involving cancer patients with high-risk of thrombosis undergoing chemotherapy. We randomly assigned patients without deep-vein thrombosis at screening to receive atorvastatin 20 mg or rivaroxaban 10 mg daily for up to 90 days. Doppler ultrasonography was performed 90 days following chemotherapy to diagnose DVT. Average cost-effectiveness analysis was performed to analyze the cost of atorvastatin compared to rivaroxaban.

Of the eighty six patients who underwent randomization, primary efficacy end point was observed in 1 of 42 patients (2.3%) in the atorvastatin group and in 1 of 44 (2.2%) in the rivaroxaban group (Odds Ratio [OR], 0.953; 95% confidence interval [CI], 0.240 to 3.971; p = 1.000). There was a significant difference in the incidence of major bleeding, 2 of 42 patients (4.8%) in the atorvastatin group and 12 of 44 (27.3%) in the rivaroxaban group (OR, 0.257; 95% CI, 0.07 to 0.94; p = 0.007). The average cost-effectiveness ratio of using atorvastatin was lower than that of rivaroxaban.

Atorvastatin did not differ significantly from rivaroxaban in reducing the incidence of DVT, lower bleeding risk, and cost-effectiveness for thromboprophylaxis in high-risk thrombosis patients with cancer undergoing chemotherapy. The presence of limited statistical power and wide confidence intervals in this study needs further study to strengthen the efficacy of atorvastatin as DVT prophylaxis in cancer patients.

ISRCTN71891829, Registration Date: 17/12/2020.

We aimed to evaluate in this study the diagnostic value of the plasmin-α2-plasmin inhibitor complex in patients with malignant tumors and venous thromboembolism (VTE).

A total of 58 patients with confirmed malignant tumors and VTE were selected, and their plasma samples were collected within 24 hours after VTE diagnosis. We also selected 60 patients with malignant tumors who were hospitalized at the same time and did not have VTE following imaging examination. Their plasma samples were collected within 24 hours after admission and were compared to those of the VTE group concerning the levels of plasmin-α2-plasmin inhibitor (PIC), thrombin-antithrombin complex (TAT), tissue-type plasminogen activator-inhibitor complex (tPAI-C), and thrombomodulin (TM). We used the receiver operator characteristic (ROC) curve to evaluate the diagnostic efficacy of each index regarding malignant tumors accompanied by VTE.

PIC, TAT, and tPAI-C were significantly higher in the group with malignant tumors and VTE compared to the group with malignant tumors without thrombosis (p =0.010, p =0.001, and p =0.003, respectively). In contrast, we found no significant difference in TM levels between the two groups (p =0.483). The area under the curve (AUC) of PIC, TAT, and tPAI-C regarding patients with malignant tumors and VTE was 0.852, 0.636, and 0.655, respectively, demonstrating diagnostic values for those cancer patients suffering VTE. PIC had the highest diagnostic efficiency in those patients with malignant tumors and VTE, while the AUC of TM was 0.537, so its diagnostic value for VTE-complicated malignant tumors was limited.

PIC has a sufficient value for the early diagnosis of VTE in patients with malignant tumors. HIPPOKRATIA 2023, 27 (2):37-40.

Cancer patients are at high risk of venous thromboembolism (VTE), a significant cause of cancer-related death. Historically, low molecular weight heparins (LMWH) were the gold standard therapy for cancer-associated VTE, but recent evidence supports the use of direct factor Xa inhibitors in cancer-associated VTE and this is now reflected in many guidelines. However, uptake of direct factor Xa inhibitors varies and guidance on the use of direct factor Xa inhibitors in specific cancer sub-populations and clinical situations is lacking. This review presents consensus expert opinion alongside evaluation of evidence to support healthcare professionals in the use of direct factor Xa inhibitors in cancer-associated VTE.

Recent guidelines, meta-analyses, reviews and clinical studies on anticoagulation therapy for cancer-associated VTE were used to direct clinically relevant topics and evidence to be systematically discussed using nominal group technique. The consensus manuscript and recommendations were developed based on these discussions.

Considerations when prescribing anticoagulant therapy for cancer-associated VTE include cancer site and stage, systemic anti-cancer therapy (including vascular access), drug-drug interactions, length of anticoagulation, quality of life and needs during palliative care. Treatment of patients with kidney or liver impairment, gastrointestinal disorders, extremes of bodyweight, elevated bleeding or recurrence risk, VTE recurrence and COVID-19 is discussed.

Anticoagulant therapy for cancer-associated VTE patients should be carefully selected with consideration given to the relative benefits of specific drugs when individualizing care. Direct factor Xa inhibitors are typically the treatment of choice for preventing VTE recurrence in non-cancer patients and should also be considered as such for cancer-associated VTE in most situations.

Lung cancer is the leading cause of cancer-related mortality worldwide with an increasing incidence in many countries. There were few studies on arterial and venous thromboembolism (ATE/VTE) in patients with metastatic lung cancer. Our study focused on the clinical characteristics of stage IV lung cancer patients with ATE or VTE to further explore the risk factors and prognosis. Patients diagnosed with metastatic lung cancer were enrolled from January 2011 to June 2019 at a tertiary hospital in Jiangyin, China. Log-rank test was used to reveal the survival for patients with ATE or VTE. Univariable analysis and multivariable logistic regression were used to study the risk factors for ATE. A total of 587 patients were enrolled in our study, including 52 patients with VTE and 48 with ATE. ATE occurred earlier than VTE. Patients with ATE had a worse prognosis. Multivariable logistic regression revealed that older age and a history of hypertension were independent risk factors for ATE. Patients with metastatic lung cancer were at high risk of VTE and ATE. ATE occurred earlier and was associated with a worse prognosis. Attention should be paid to metastatic lung cancer patients who may develop thromboembolism, especially ATE.

Current technologies for the real-time analysis of biomarkers in vivo, such as needle-type microelectrodes and molecular imaging methods based on exogenous contrast agents, are still facing great challenges in either invasive detection or lack of active control of the imaging probes. In this study, by combining the design concepts of needle-type microelectrodes and the fluorescence imaging method, a new technique is developed for detecting biomarkers in vivo, named as "optically controlled virtual microsensor" (OCViM). OCViM is established by the organic integration of a specially shaped laser beam and fluorescent nanoprobe, which serve as the virtual handle and sensor tip, respectively. The laser beam can trap and manipulate the nanoprobe in a programmable manner, and meanwhile excite it to generate fluorescence emission for biosensing. On this basis, fully active control of the nanoprobe is achieved noninvasively in vivo, and multipoint detection can be realized at sub-micrometer resolution by shifting a nanoprobe among multiple positions. By using OCViM, the overexpression and heterogenous distribution of biomarkers in the thrombus is studied in living zebrafish, which is further utilized for the evaluation of antithrombotic drugs. OCViM may provide a powerful tool for the mechanism study of thrombus progression and the evaluation of antithrombotic drugs.

Background and aim. Cancer and atrial fibrillation (AF) may be associated, and anticoagulation, either with vitamin K antagonists (VKAs) or direct oral anticoagulants (DOACs), is necessary to prevent thromboembolic events by reducing the risk of bleeding. The log incidence rate ratio (IRR) and 95% confidence interval were used as index statistics. Higgin’s I2 test was adopted to assess statistical inconsistencies by considering interstudy variations, defined by values ranging from 0 to 100%. I2 values of less than 40% are associated with very low heterogeneity among the studies; values between 40% and 75% indicate moderate heterogeneity, and those greater than 75% suggest severe heterogeneity. The aim of this meta-analysis was to compare the safety and efficacy of VKAs and DOACs in oncologic patients with AF. Methods. A meta-analysis was conducted comparing VKAs to DOACs in terms of thromboembolic events and bleeding. A meta-regression was conducted to investigate the differences in efficacy and safety between four different DOACs. Moreover, a sub-analysis on active-cancer-only patients was conducted. Results. A total of eight papers were included. The log incidence rate ratio (IRR) for thromboembolic events between the two groups was −0.69 (p < 0.005). The meta-regression did not reveal significant differences between the types of DOACs (p > 0.9). The Log IRR was −0.38 (p = 0.008) for ischemic stroke, −0.43 (p = 0.02) for myocardial infarction, −0.39 (p = 0.45) for arterial embolism, and −1.04 (p = 0.003) for venous thromboembolism. The log IRR for bleeding events was −0.43 (p < 0.005), and the meta-regression revealed no statistical difference (p = 0.7). The log IRR of hemorrhagic stroke, major bleeding, and clinically relevant non-major bleeding between the VKA and DOAC groups was −0.51 (p < 0.0001), −0.45 (p = 0.03), and 0.0045 (p = 0.97), respectively. Similar results were found in active-cancer patients for all the endpoints except for clinically-relevant non-major bleedings. Conclusions. DOACs showed better efficacy and safety outcomes than VKAs. No difference was found between types of DOACs.

Coagulation regulates angiogenesis in cancer, and is associated with tumor development and metastasis. To date, there have been no studies quantifying the state of intra-tumoral coagulation. We measured intra-tumoral coagulation gene expression using the "Hallmark-COAGULATION" gene set in the MSigDB, performing gene set variation analysis and then assigning a "coagulation score" to quantify gene expression. Clinical, histologic, and genetic data were analyzed in 807 gastric cancer patients from the TCGA_STAD and GSE84437 databases. Tumors with increased expression of pro-coagulation genes were consistently associated with higher AJCC T-categories (p = 0.018), lymph node metastasis (p = 0.036), and stage (p = 0.006) in both cohorts. Patients with high coagulation scores were found to have worse disease-specific survival and overall survival (OS) (p = 0.019 and 0.011, respectively) in TCGA, and worse OS in GSE84437 cohort (p = 0.012). Higher expression of pro-coagulation genes correlated with increased intra-tumoral angiogenesis, as well as increased proportions of lymphatic and microvascular endothelial cells, endothelial cells, and pericytes, calculated by xCell algorithm. High coagulation scores were significantly associated with low tumor mutation burden, but not with intratumor heterogeneity and homologous recombination deficiency. Gastric cancers with high coagulation scores contained higher amounts of M1 macrophages and dendritic cells, and low numbers of Th1 cells (all P<0.001). Genes for epithelial mesenchymal transition (EMT), myogenesis, apical junction, transforming growth factor (TGF)-β signaling, and angiogenesis were enriched in high coagulation score-gastric cancers (all false discovery rate <0.25). In conclusion, gastric cancers expressing higher levels of pro-coagulation genes demonstrate increased angiogenesis, EMT, TGF-β signaling and worse patient prognosis.