Increase In Incidence Of Venous Thromboembolism Research Articles

#435 Endothelial activation and inflammation in chronic kidney disease (CKD): role of neutrophil extracellular traps (NETs)

Abstract Background and Aims Advanced chronic kidney disease (CKD), especially in stages 4-5, amplifies cardiovascular disease (CVD) risk by around 50%. This heightened susceptibility is linked to a 1.5 to 3-fold increase in venous thromboembolism incidence, driven by coagulation dysregulation and heightened inflammation. During inflammation, neutrophils can release extracellular traps (NETs), that was described contribute to endothelial damage, through adhesion molecule elevation, and tissue factor (TF) secretion, exacerbating thrombosis. Additionally, NETs interact with von Willebrand Factor (vWF) and factor XII, further amplifying thrombus formation and the activation of the intrinsic coagulation pathway. The aim of this study was to observe whether NETs may contribute to increased CVD risk in CKD patients by inducing endothelial activation and thromboinflammatory responses to a larger extent compared to NETs from healthy donors. Method For that, neutrophils were isolated from healthy donors’ and CKD patients’ (stages 3-5 HD) peripheral blood, and NETs were collected by stimulating neutrophils with PMA for 3.5 hours. Human aortic endothelial cells (HAoECs) were subsequently exposed to NETs for 3 to 24 hours, followed by gene expression analysis with a focus on inflammation, endothelial activation, and prothrombotic markers. Additionally, protein analysis of the supernatant was conducted using ELISA. All experiments were performed under ethical protocol EK 225-21 from the University Hospital of Aachen. Results Exposure to both healthy NETs as well as the ones isolated from CKD patients resulted in a notable upregulation of endothelial activation (VCAM-1), prothrombotic (TF), and inflammatory (IL-6) gene expression within 3 hours, without difference between healthy and CKD conditions. On the other hand, when examining the cellular supernatant, a significantly higher increase in vWF secretion was observed upon treatment with CKD-NETs compared to healthy NETs. Furthermore, while secretion of the inflammatory cytokine IL-6 presented a comparable increase upon treatment with NETs derived from healthy and CKD neutrophils, IL-1β secretion was markedly enhanced after CKD-NET treatment in comparison to healthy NETs. Conclusion In summary, our findings suggest that NETs exert a significant influence on endothelial cells, contributing to increased thromboinflammatory activation. Notably, CKD-NETs evoked a more rapid impact on the endothelium, accompanied by increased secretion of IL-1β and vWF, and underlying mechanisms will be further investigated.

Prognostic Factors Associated with Venous Thromboembolism Following Traumatic Injury: A Systematic Review and Meta-Analysis.

Trauma patients are at increased risk of venous thromboembolism (VTE), including deep venous thrombosis (DVT) and/or pulmonary embolism (PE). We conducted a systematic review and meta-analysis summarizing the association between prognostic factors and the occurrence of VTE following traumatic injury. We searched the EMBASE and MEDLINE databases from inception to August 2023. We identified studies reporting confounding adjusted associations between patient, injury or post-injury care factors and risk of VTE. We performed meta-analyses of odds ratios (ORs) using the random effects method and assessed individual study risk of bias using the QUIPS tool. We included 31 studies involving 1,981,946 patients. Studies were predominantly observational cohorts from North America. Factors with moderate or higher certainty of association with increased risk of VTE include older age, obesity, male sex, higher injury severity score, pelvic injury, lower extremity injury, spinal injury, delayed VTE prophylaxis, need for surgery and tranexamic acid use. After accounting for other important contributing prognostic variables, a delay in the delivery of appropriate pharmacologic prophylaxis for as little as 24 to 48 hours independently confers a clinically meaningful two-fold increase in incidence of VTE. These findings highlight the contribution of patient predisposition, the importance of injury pattern, and the impact of potentially modifiable post-injury care on risk of VTE after traumatic injury. These factors should be incorporated into a risk stratification framework to individualize VTE risk assessment and support clinical and academic efforts reduce thromboembolic events among trauma patients.Study TypeSystematic Review & Meta-Analysis. Level II.

Determining the Causal Effect of Statins on Reducing the Incidence of Venous Thromboembolism after Ankle Fractures

Category: Ankle; Other Introduction/Purpose: It can be challenging to decide when to give preventative medication for venous thromboembolism (VTE). It is challenging to identify VTE in its early phases, and surgeons disagree on when prophylaxis should be given and when to suspect VTE. Additionally, patients who are not at a high risk of VTE are advised not to take prophylaxis due to the potential risk of bleeding adverse events and the evidence does not fully support providing prophylaxis in isolated foot and ankle procedures (BAE). The effectiveness of prevention, particularly in isolated foot and ankle fractures, is debatable, and research into how patients react to statins is necessary. By utilizing causal inference techniques, this research simulates a randomized control trial (RCT) from observational data. Methods: Out of a total of 1,175 patients, 238 had confirmed VTE 180 days after the incidence of ankle fracture (Case group, n=238). The inclusion criteria were 1- ankle fracture diagnosed by a physician and confirmed radiologically via X-ray or CT scan; 2- Age of 18 years or older; 3- Symptomatic VTE confirmed by a clinician and through radiologic (Duplex ultrasound, CT angiography, and/or angiography). To infer causal effects, we took the three following steps: first, the causal diagram must be created. Second, the set of variables necessary for causal inference must be identified. Third, the average treatment effect should be estimated for different treatment regimens. Results: Table 1 shows the incidence of VTE among patients who had VTE chemoprophylaxis. A non-significant 2.9% increase in VTE incidence was found, 95% CI [-1%, 7%]. The results state that, if a patient is already taking Statins, the incidence of VTE is reduced by 1%, 95% CI [-4.2%, 2.8%] as compared to patients who are not taking the drug which is not statistically significant. This indicates that there is no significant difference between administering VTE prophylaxis or not, in patients that are already consuming Statins. On the contrary, for patients in the sample that are not already taking Statins, the VTE incidence increases by 6%, 95% CI [1.6%, 10%] compared to no treatment administration which is significant since the confidence interval does not contain 0. Conclusion: Our findings provide more evidence that VTE prophylaxis may not, on average, be successful in lowering the incidence of VTE after ankle fracture, particularly in individuals who do not take Statins. To put it another way, doctors may decide not to give extra prophylaxis to avoid VTE in isolated ankle fractures if a patient is on Statins. Here, we established the causal inference methodology that can help us reproduce the results of an expensive RCT.

MP43-08 VENOUS THROMBOEMBOLISM RISK IN TESTOSTERONE TREATED MEN WITH AND WITHOUT KLINEFELTER SYNDROME

You have accessJournal of UrologyCME1 Apr 2023MP43-08 VENOUS THROMBOEMBOLISM RISK IN TESTOSTERONE TREATED MEN WITH AND WITHOUT KLINEFELTER SYNDROME Christopher Lau, Yunzhe Zhang, Bethany Gabriel, Jesufikunayomi Ifeoluwa, and Tet Yap Christopher LauChristopher Lau More articles by this author , Yunzhe ZhangYunzhe Zhang More articles by this author , Bethany GabrielBethany Gabriel More articles by this author , Jesufikunayomi IfeoluwaJesufikunayomi Ifeoluwa More articles by this author , and Tet YapTet Yap More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000003289.08AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: There is a higher risk of VTE in Klinefelter syndrome (KS) (∼17%) compared to the general population (∼0.1%). The risk of venous thromboembolism (VTE) as an adverse effect of testosterone therapy (TT) has been hypothesised, however there is limited data on this. TT is a common treatment for symptom management in KS, and is potentially a factor in higher VTE rates seen in KS. This study aims to evaluate the association between TT in both men with and without KS and VTE. METHODS: A literature review was performed following PRISMA guidelines, using sites such as BMJ, PubMed and ScienceDirect. Study searches, selection, data collection and analysis were carried out by four researchers independently and cross reviewed. 27 studies were selected and results from 6, which were specific to TT and VTE, were included [Table 1]. Significance level was set at p≤0.05. To assess risk of bias, tools such as Newcastle-Ottawa scale were used, and heterogeneity was found. RESULTS: The incidence of VTE in non-KS on TT ranged from 0.6-5.6% (n=2224). The incidence of VTE in KS on TT ranged from 31.3-40.0% (n=135). The background risk was 0.12% and 17.0% for the non-KS and KS groups respectively. Overall, there was a statistically significant increase in incidence of VTE in men taking TT both in the KS [χ2 = 9.95, p<.05] and non-KS [χ2 = 545.66, p<.05] patient groups. However, no statistically significant difference in VTE between the different routes of administration of TT in both the KS [χ2 = 0.12, p=.729485] and non-KS [χ2 = 7.29, p=.06309] patient groups. CONCLUSIONS: Overall, a significant increase in incidence of VTE was observed in men taking TT both in the KS and non-KS patient groups. However, similar rates of VTE between the different routes of administration of TT. Owing to the highly variable follow up period of testosterone treated men, a transient increase in risk of VTE in the first 6 months of initiating treatment was observed by a case control study. It is possible that this change was also observed in the results and therefore more data would be required exploring the long term use of TT and VTE risk. Source of Funding: N/A © 2023 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 209Issue Supplement 4April 2023Page: e604 Advertisement Copyright & Permissions© 2023 by American Urological Association Education and Research, Inc.MetricsAuthor Information Christopher Lau More articles by this author Yunzhe Zhang More articles by this author Bethany Gabriel More articles by this author Jesufikunayomi Ifeoluwa More articles by this author Tet Yap More articles by this author Expand All Advertisement PDF downloadLoading ...

Actual questions about the prevention of venous thromboembolism in cancer patients receiving chemotherapy

Cancer patients have a 2-7 fold increased risk of venous thromboembolism compared with the general population and, since 1990, this is associated with significant morbidity and mortality. This review summarizes the current knowledge on venous thromboembolism and cancer. Notably, the risk of venous thromboembolism varies depending on the type and stage of cancer. For instance, pancreatic and brain cancer patients have a higher risk of venous thromboembolism than breast and prostate cancer patients. Moreover, patients with metastatic disease have a higher risk than those with localized tumors. Tumor-derived procoagulant factors, cytokines and growth factors may directly and indirectly enhance venous thromboembolism. Chemotherapy produces ~6,5 fold increase in venous thromboembolism incidence in cancer patients compared to the general population. Prevention of this complication is challenging. The authors review the development of guidelines concerning venous thromboembolism prevention in hospitalized and also in ambulatory cancer patients treated with chemotherapy. Current guidelines recommend the use of low-molecular-weight heparin. Understanding the underlying mechanisms may allow the development of new therapies to safely prevent venous thromboembolism in cancer patients.

Safety assessment of raloxifene over eight years in a clinical trial setting

ABSTRACTObjective: Osteoporosis is a chronic disorder that warrants long-term therapy. If benefits are to outweigh risks, the long-term safety profiles of these therapies must be favorable. The aim of this study was to assess the safety of raloxifene over 8 years in 4011 postmenopausal women with osteoporosis in a clinical trial setting through adverse event reporting.Methods: Data analyzed comprised all reported adverse events collected at each visit of both the Multiple Outcomes of Raloxifene Evaluation (MORE) trial, and the subsequent Continuing Outcomes Relevant to Evista (CORE) trial. MORE was an international, 4‐year double-blind, randomized, placebo-controlled study, designed to assess the effect of raloxifene on bone mineral density and vertebral fracture incidence in 7705 (placebo, 2576; raloxifene, 5129) postmenopausal women with osteoporosis. Breast cancer was a secondary endpoint. Based on the breast cancer findings of MORE, the CORE trial, a 4‐year double-blind, placebo-controlled trial of a subset of MORE participants, was subsequently conducted. CORE enrolled 4011 (placebo, 1286; raloxifene, 2725) participants and was designed to examine raloxifene's effect on breast cancer incidence. Safety analyses were performed using the intention-to-treat principle, and comparison between therapies was analyzed using a two-sided Fisher's exact test.† Evista is a registered trade name of Eli Lilly and Company, Indianapolis, USAResults: Over the 8 years of follow-up of 4011 women, there was no difference in all-cause mortality or hospitalization incidence between raloxifene and placebo groups ( p > 0.1). Excluding breast cancer and non-melanoma skin cancer, cancer incidence was 4.6% and 6.3% in the raloxifene and placebo group, respectively ( p = 0.027). Raloxifene was associated with a 1.7-fold increase in venous thromboembolism incidence (95% confidence interval 0.93–3.14), with an absolute risk difference of 0.9 per 1000 woman-years. There was no difference in the incidence of myocardial infarction, stroke, uterine cancer, endometrial hyperplasia, ovarian cancer or postmenopausal bleeding between the raloxifene and placebo treatment groups ( p > 0.5). Uterine polyps, hot flushes and muscle cramps were more common in those receiving raloxifene versus placebo ( p = 0.028, p < 0.001, and p = 0.008, respectively).Conclusion: These 8‐year data support the known clinical safety profile of raloxifene, established in the MORE trial.

The Effect of Patient Age and Calendar Year on the Incidence of Idiopathic vs. Secondary Venous Thromboembolism (VTE): A Population-Based Cohort Study.

If the observed dramatic increase in VTE incidence with advancing age is due to increased VTE risk factor exposure (i.e., secondary VTE), the incidence of idiopathic VTE should not vary with age or calendar year.Objective: To estimate the incidence of idiopathic and secondary VTE by age and by calendar year.Methods: Using the resources of the Rochester Epidemiology Project, we identified the inception cohort of Olmsted County, MN, residents with a first lifetime VTE during the 30-year period, 1966–1995 (n=2761). For each case, we reviewed the complete medical records in the community for 48 baseline clinical characteristics that are commonly-accepted risk factors for VTE. We categorized VTE cases as idiopathic (n=305) if no such characteristics were present; the remaining cases were categorized as secondary. Age- and sex-specific incidence rates were calculated using idiopathic or secondary VTE cases as the numerator, and age-, sex- and calendar year-specific estimates of the population of Olmsted County as the denominator.Results: The incidence of both idiopathic and secondary VTE increased exponentially with age for both men and women (p<0.001). Over the 30-year study period, the age-adjusted incidence of idiopathic VTE was essentially constant among men (from 19.0 to 17.1 per 100,000 men-years for 1966–70 and 1990–95, respectively), but decreased markedly among women (from 18.5 to 3.6 per 100,000 woman-years for 1966–70 and 1990–95, respectively; p=0.005 for the interaction).Conclusions: The dramatic increase in VTE incidence with age likely reflects the biology of aging, although as yet unidentified VTE risk factors cannot be excluded. The reason for the decreased incidence of idiopathic VTE over the last 30 years among women is unclear.

VAD-t (Vincristine, Adriamycin, Dexamethasone and Low-Dose Thalidomide) Is an Effective Initial Therapy with High Response Rates for Patients with Treatment Naïve Multiple Myeloma (MM).

Recent understanding of MM biology suggests that MM cells rely on their microenvironment for disease progression and dissemination. MM cell interaction with stromal cells in the bone marrow microenvironment fosters chemotherapy resistance. Targeting the microenvironment with novel biologic agents such as thalidomide (T) has shown encouraging clinical results in patients with previously untreated as well as relapsed/refractory MM. We have previously shown here that VAD plus low dose T (t) is an effective salvage regimen for VAD refractory pts. We report the preliminary results of an ongoing phase II trial studying a combined chemoimmunotherapeutic approach - standard VAD plus t (200 mg) in treatment-naïve MM pts. This regimen was designed to target concurrently the malignant cell and its microenvironment. MM pts, ≥ Stage I with no prior therapy were eligible for study. Monthly infusional VAD (standard dose) was given for 4 cycles every 28 days concurrently with t for 4 months. t (100mg) was started 1 wk prior to VAD and was escalated in 1–2 wks to 200mg. Pts were evaluated for response after each cycle and after cycle 4 using SWOG criteria. Pts characteristics include: enrolled n=16, 8M, 8F; median age 58 yrs range 46–77; Stage III disease n=11, Stage II, n=3 and Stage 1, n=1; and Median B2M, 1.9 mg/L (range 1.2–11.5). Low dose coumadin (1–2 mg) was used for venous thromboembolism (VTE) prophylaxis, t was also held during the 4 days of each infusion of VAD. All pts are evaluable for toxicity and 11 are evaluable for response after completing 4 cyc. 10/11 (91%) responded clinically; CR, n=3, PR, n=7. One pt had progressive disease. Three pts with responding disease were removed from study for Grade III toxicity (1 adriamycin associated cardiomyopathy, 1 pulmonary hypertension and 1 recurrent infections) but are not included in response evaluation. Toxicities: fatigue (Gr. II) was the most common side effect (25%) and DVT was noted in 2 (12%). All pts eligible for stem cell (SC) transplant (n=7), were able to collect adequate amount of SC post VAD-t. Preliminary results of this study suggest that VAD-t is an effective and well-tolerated regimen with improved ORR compared to standard VAD regimen in pts with treatment naïve MM. No increase in incidence of VTE was noted with the combination. Adequate SC collection was achieved in transplant eligible pts. Accrual is ongoing on this study and updated results will be presented at the annual meeting.