High Risk Of Venous Thromboembolism Research Articles

Event rates and risk factors for venous thromboembolism and major bleeding in a population of hospitalized adult patients with acute medical illness receiving enoxaparin thromboprophylaxis

BackgroundWe aimed to describe the event rates and risk-factors for symptomatic venous thromboembolism (VTE) and major bleeding in a population of hospitalized acutely ill medical patients. MethodsPatients ≥40 years old and hospitalized for acute medical illness who initiated enoxaparin prophylaxis were selected from the US Optum research database. Rates of symptomatic VTE and major bleeding at 90-days were estimated via the Kaplan-Meier (KM) method. Risk factors were identified via the Cox proportional hazards model. ResultsA total of 123,022 patients met the selection criteria. The KM rates of VTE and major bleeding at 90-days were 3.5 % and 2.2 %, respectively. Among subgroups, the risk of VTE varied from 3.0 % in patients with ischemic stroke to 6.9 % in patients with a cancer-related hospitalization, and the risk of major bleeding varied from 1.9 % in patients with inflammatory conditions to 3.6 % in patients with ischemic stroke. Key risk factors for VTE were prior VTE (HR=4.15, 95 % confidence interval [CI] 3.80–4.53), cancer-related hospitalization (HR=2.35, 95 % CI 2.10–2.64), and thrombophilia (HR=1.64, 95 % CI 1.29–2.08). Key risk factors for major bleeding were history of major bleeding (HR=2.17, 95 % CI 1.72–2.74), history of non-major bleeding (HR=2.46, 95 % CI 2.24–2.70), and hospitalization for ischemic stroke (2.42, 95 % CI 2.11–2.78). ConclusionThere is substantial heterogeneity in the event rates for VTE and major bleeding in acute medically ill patients. History of VTE and cancer related hospitalization represent profiles with a high risk of VTE, where continued VTE prophylaxis may be warranted.

Developing the Form and Content of Implementation Strategies to Prevent Venous Thromboembolism for Ambulatory Patients with Cancer

Introduction To prevent venous thromboembolism (VTE) in people with cancer, guidelines recommend risk-assessment for those receiving systemic therapy and anticoagulation (AC) prophylaxis for those at high risk of VTE. However, these recommendations are significantly underused in clinical practice. Our prior work demonstrated barriers and facilitators contributing to this underuse and identified potential implementation strategies to address these barriers. The objective of this study was to develop the form and content of targeted implementation strategies promoting the uptake in clinical practice of guideline-recommendations for VTE prevention for ambulatory patients with cancer. Methods We conducted multidisciplinary stakeholder focus group discussions and semi-structured patient interviews to iteratively design the form and content of five implementation strategies (Table 1): (1) Conduct clinician education and training on risk-assessment models and anticoagulation thromboprophylaxis; (2) Adapt electronic health records (EHR) to provide interactive assistance; (3) Develop and distribute educational materials for clinicians about the Khorana score, VTE risk, and AC counseling; (4) Develop and distribute educational materials for patients; and (5) Audit and feedback. Stakeholders included oncologists, classical hematologists, an oncology clinical pharmacist, oncology advanced practice providers, and oncology patients, in academic and community-based settings within a single health care system. We conducted the clinician focus groups iteratively: in the first session we reviewed guidelines and evidence to support the use of risk assessment and AC prophylaxis in patients with cancer and shared barriers and facilitators identified in our earlier work. During subsequent sessions, we iteratively designed the form and content of the implementation strategies. In the final session, clinicians were presented a finalized prototype of the implementation strategies and asked to perform exploratory usability testing through simulated patient care encounters. Individual semi-structured interviews were conducted with patients to obtain feedback on the design of the implementation strategies and patient-education resources. Results A workflow for integration of risk-assessment and relevant prophylaxis in clinical practice was created based on participant feedback. Details for selected implementation strategies are shown in Table 1. For EHR support, stakeholders recommended the risk-assessment component be integrated within chemotherapy order sets. In addition, they recommended incorporating aid for AC management within the EHR, including a method to assess bleeding risk, pre-populated options for AC thromboprophylaxis, provision of easily accessible links to resources for peri-operative/procedure AC management, and a list of interactions between anticoagulants and common drugs used in oncology practice. Clinician stakeholders also recommended - and subsequently approved - standard phrases available to incorporate into the EHR documentation, both to guide decision-making and to serve as a reminder to re-assess in future visits. For education resources (clinician and patient), clinicians wanted education resources to be concise, and for the patient-facing resource, to be provided to patients both in existing “chemotherapy education” booklets and sent in after-visit appointment instructions. Regarding audit and feedback, clinicians recommended a personalized report card comparing their use of appropriate VTE prevention to their peers. After reviewing the patient-facing education documents, patients recommended simpler, straightforward language and clarifications for the VTE and AC patient education resources based on their past experiences. Conclusions With multidisciplinary stakeholder input from clinicians and patients, we developed a set of implementation strategies designed to address barriers to uptake of VTE prevention recommendations in oncology clinics. Next steps are to test the implementation strategies in clinical practice to measure impact on increasing these evidence-based interventions.

Updated Meta-Analysis of Randomized Controlled Trials on Primary Outpatient Thromboprophylaxis (POTP) in Patients with Lung Cancer Receiving Chemotherapy

Introduction Lung cancer (LC) is the leading cause of cancer mortality in the USA. Thrombosis is the second leading cause of death in cancer patients and in recent years, several studies have been conducted to determine beneficial effect of POTP in reduction of VTE (venous thromboembolism) rate in solid cancer patients with the aim to improve the overall survival. We performed an updated meta- analysis of randomized control trials (RCTs) to determine the benefit and risk of POTP with low-molecular weight heparins (LMWHs) and direct oral anticoagulants (DOACs) in patients with LC receiving chemotherapy. Methods We performed a comprehensive literature search using MEDLINE and EMBASE databases through June 30, 2023. The references of all potential studies were also reviewed for any additional relevant studies. The RCTs with reduction in VTE as a primary or secondary endpoint and the major bleeding (MB) as a safety outcome were incorporated in the analysis. Mantel-Haenszel (MH) method was used to calculate the estimated pooled risk ratio (RR), and risk difference (RD) with 95% confidence interval (CI). Heterogeneity was assessed with Cochran's Q- statistic. Fixed effects model was applied. Results A total of 5,434 patients with LC from five RCTs and subgroups of another five RCTs were included in our meta-analysis. The prophylactic doses of bemiparin, certoparin, dalteparin, nadroparin, semuloparin and tinzaparin, intermediate dose of enoxaparin and prophylactic dose of rivaroxaban and apixaban were used in the studies. The duration of LMWH and DOAC ranged from 3 to 6 months. The randomization ratio was 2 to 1 in PROTECHT study and 1 to 1 in all other studies. The I 2 statistic for heterogeneity was 0, suggesting homogeneity among RCTs. The VTE incidence was 114 (4.12%) in PATP group and 207 (7.8%) in control group with a RR of 0.53 (95% CI: 0.43 to 0.67, P < 0.00001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.00001) with an estimate of the number needed to treat (NNT) of 25 to prevent one VTE event. In subgroup analysis of PATP trials treated with LMWHs in study arm, VTE events were reported in 112 (4.2%) in PATP group and 202 (7.9%) in control group with a RR of 0.54 (95% CI: 0.43 to 0.67, P < 0.00001). The absolute RD in VTE was -0.04 (95% CI: -0.05 to -0.02, P < 0.00001). In subgroup analysis of PATP trials treated with DOACs in study arm, VTE events were reported in 2 (2.2%) in PATP group and 5 (5%) in control group with a RR of 0.46 (95% CI: 0.09 to 2.31, P=0.35). The absolute RD in VTE was -0.03 (95% CI: -0.08 to -0.03, P=0.36). Major bleeding (MB) events were reported in 34 (1.6%) patients in POTP group compared to 17 (0.86%) in control group according to an analysis of 7 RCTs. The pooled relative risk for MB was statistically significant at 1.84 (95% CI: 1.06 to 3.22, P = 0.03). Conclusions Our analysis showed that the relative risk reduction is 47% with a NNT of 25 to prevent one VTE with statistically significant increase in MB events in ambulatory patients with LC by providing POTP. In our subgroup meta-analysis of POTP with DOACs, there was no statistically significant difference in reduction of VTE in LC patients with Khorana Score ≥2. Hence, the selection of appropriate patients who are high risk for VTE is crucial and further studies are required to define high risk subsets of LC patients receiving chemotherapy who may benefit from POTP.

Derivation of a Risk Prediction Model for Venous Thromboembolism in Adult Patients with Acute Myeloid Leukemia

Background: Venous thromboembolism (VTE) is a well-established complication of malignancy associated with high morbidity. Many validated scoring systems exist to predict risk of VTE in patients with solid tumors. However, there are no models that can prospectively identify patients at high risk for the development of VTE in acute myeloid leukemia (AML). The purpose of this study was to determine risk factors for the development of VTE in a large cohort of AML patients and to develop a risk stratification model to predict VTE risk in this patient population. Methods: Adult patients presenting to the University of Wisconsin-Madison with newly-diagnosed AML from 1/1/2010 through 12/31/2021 were included in this retrospective cohort study. The primary end point was VTE within one year of diagnosis. Univariate logistic regression models were used to assess the association of each variable with development of VTE. Multivariate analysis was then completed using 16 candidate variables including demographics (sex, race, age at diagnosis), comorbidities (hypertension, diabetes, coronary artery disease, asthma/COPD), body mass index (BMI), Eastern Cooperative Oncology Group performance status (ECOG PS), history of solid organ or hematologic malignancy, smoking status, indwelling venous catheter, history of VTE, and baseline laboratory values (white blood cell count, hemoglobin, platelet count). Non-normally distributed continuous candidates were log10-transformed, then stepwise selection was used on a training set to choose predictive variables to construct a risk score to predict VTE within one year of AML diagnosis. Results: 326 patients with AML were included in the analysis. The median age at diagnosis was 60 years (range 19-92 years), 55% of the study population was male, and 94% were Caucasian race. 59 patients (18%) experienced VTE within one year of diagnosis. Age at diagnosis (OR 0.98, 95% CI, 0.963-0.998, p=0.033), BMI (OR 1.058, 95% CI, 1.02-1.10, p=0.005), hypertension (OR 0.522, 95% CI, 0.29-0.96, p=0.035) and platelets (OR 3.16, 95% CI, 1.44-6.94, p = 0.004) were individually associated with VTE. In a subgroup analysis of 278 patients with next generation sequencing data available, mutations in DNA methylation genes (DNMT3A, DNMT1, IDH1, IDH2, TET2) were associated with an increased risk of VTE (OR 1.911, 95% CI 1.017-3.591, p=0.0442, Table 1). A multivariate logistic regression model identified six independent predictors of VTE including platelet count >150,000 (OR 1.64, 95% CI 0.65-4.14, p=0.2953), BMI >25 (OR 3.10, 95% CI 1.22-7.86, p=0.0173), hypertension (OR 2.17, 95% CI 1.03-4.55, p=0.0410), history of other cancer (OR 1.72, 95% CI, 0.74-4.01, p=0.2109), diabetes (OR 2.05, 95% CI 0.73-5.73, p=0.1718), and ECOG PS (OR 1.33, 95% CI, 0.66-2.65, p=0.4263). Subsequently, a risk score was constructed from the multivariable model (3*platelets>150 + 8*BMI>25 + 5*NoHTN + 3*NoOtherCancer + 4*Diabetes + 1*ECOG0). Patients were categorized into three groups: low (score<9), moderate (9score<12), and high (score) risk of developing VTE (Table 2). Rates of VTE within one year of AML diagnosis were 3.2%, 16.4%, and 23.6% in the low, moderate, and high risk groups respectively. The model had an external AUC=0.704 when applied to our test set. Conclusions: Our study demonstrates a high rate of early VTE in patients with AML at 18%, highlighting the importance of identifying those at higher risk which would allow for early screening, patient education, and consideration of thromboprophylaxis. On multivariable analysis, we found that normal or elevated platelet count >150, BMI 25, and diabetes were associated with an increased risk of early VTE. Surprisingly, higher ECOG PS, history of malignancy, and hypertension were associated with a decreased risk of early VTE in our cohort. A risk prediction model incorporating these findings was able to identify patients with low, moderate, and high risk of VTE. This model may help with clinical decision making, such as the consideration of thromboprophylaxis for patients with a moderate or high risk score. However, prospective validation of this model in a larger cohort of patients is needed. In summary, we propose a risk prediction model for the development of VTE in AML that can now be validated in order to provide optimal supportive care for this patient population.

Bleeding Risk from Anticoagulant Thromboprophylaxis in Patients with Multiple Myeloma

Introduction: Patients with multiple myeloma (MM) have a high risk of venous thromboembolism (VTE) due to unique disease-related (i.e., vascular inflammation, hyperviscosity) and treatment-related factors (i.e., immunomodulatory drugs [IMiDs], high-dose dexamethasone). Thromboprophylaxis is recommended for most patients starting MM therapy. Anticoagulants are preferred over aspirin except in patients at low risk for VTE. However, compliance with prophylaxis guidelines is low. The risk of bleeding from thromboprophylaxis is not well described in these patients so an excessive perceived risk may influence clinicians' practice. We conducted a real-world analysis of bleeding complications from VTE prophylaxis in MM. Methods: The IBM MarketScan Commercial Claims Database was used to identify MM cases between 2013 and 2021. Cases required MM diagnosis from 1 inpatient or 2 outpatient claims, based on ICD-9 or ICD-10 codes, and MM-specific therapy started between 7 days before and 90 days after index diagnosis code, based on HCPCS codes and prescription records. Those with preexisting VTE, atrial fibrillation or stroke were excluded. Thromboprophylaxis was defined as at least 1 prescription for warfarin, low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOAC) within 30 days of diagnosis. Major bleeding was defined as bleeding requiring hospitalization using inpatient ICD codes previously validated (Cunningham algorithm). Patients were followed from end of prophylaxis exposure window (index MM + 30 days) to first major bleeding event, disenrollment (due to death or other reasons) or December 31, 2021. Descriptive statistics were used to calculate rates of bleeding. Cox regression was used to assess the risk of bleeding from thromboprophylaxis and define risk factors associated with major bleeding. Results: We included 6,656 patients diagnosed and treated for MM, with mean age 62.7 years and 55.3% males. Although over 50% of the population would have had a high thrombotic risk based on consensus guidelines, concurrent anticoagulant prophylaxis was prescribed in only 6.6% (436). Prophylaxis agent of choice was warfarin in 23% (102), LMWH in 39% (169), and DOAC in 38% (165), respectively. There was a trend over time favoring DOAC over other agents (25% increase in DOAC use vs. other agents per year on average, p<0.01). Patients on prophylaxis had a higher rate of IMiD-based therapy (63.8% vs. 46.7%, p<0.01) and lower concomitant anti-platelet use (2.1% vs. 4.7%, p=0.01) than those not receiving prophylaxis. There were no differences in age/sex distribution, Charlson comorbidity index (CCI) or history of bleeding between groups. With a median 1.3 years follow-up, the incidence of major bleeding among MM patients receiving VTE prophylaxis was 1.4% or 7.8 bleeding events per 1,000 person-years. This was numerically but not statistically lower than the incident bleeding rate in patients not receiving prophylaxis: 1.8% or 10.1 events per 1,000 person-years. Table 1 shows risk factors for bleeding in this MM population, adjusting for age and sex, including higher age (per 10-year increase, HR 1.38), higher CCI (per SD increment, HR 1.18), history of bleeding (HR 1.54), hypertension (HR 1.87), and renal disease (HR 1.56). IMiD-based MM therapy was associated with decreased risk of bleeding (HR 0.69). Table 2 shows the estimated bleeding risk associated with prophylaxis across several models. No statistically significant association was identified between major bleeding and anticoagulant prophylaxis. Discussion: In a real-world analysis of commercial claims data, the risk of major bleeding associated with VTE prophylaxis in patients with MM undergoing cancer therapy is low and no significant increase in bleeding risk was identified for concurrent anticoagulant use. The rate of major bleeding events appears to be comparable between patients who receive VTE prophylaxis and those who do not. Nevertheless, underutilization of VTE prophylaxis is frequent. Higher CCI, bleeding history, hypertension, and renal disease were clinical factors associated bleeding risk, which may be included in models to help clinicians assess individual patient's risk and guide clinical decisions.

Cellular Components in Whole Blood Contribute to the Development of Thromboembolic Events in Patients with Pancreatic Cancer

Introduction Thromboembolic disease is a major complication in patients with pancreatic ductal adenocarcinoma (PDAC), causing morbidity and mortality. One in five patients with newly diagnosed PDAC develops a venous thromboembolism (VTE), which is associated with a decreased overall survival time . Patients with PDAC often have altered blood cell counts, which are further affected by systemic therapy. The high thromboembolic risk in patients with PDAC may be caused by pro-coagulant effects of pancreatic cancer on blood cells. Currently, there are no risk assessment tools or biomarkers available that can identify PDAC patients at highest risk of VTE. Aims To investigate the impact of PDAC on blood cell dependent coagulation, to characterize the high thrombosis risk in PDAC patients.To predict thromboembolic events in patients with PDAC using blood cell dependent assays, performed in whole blood. Methods Patients with locally advanced or metastatic PDAC (n=18) were included in a prospective, observational, case-control study (TROCOPAC study). At inclusion, before the initiation of chemotherapy, blood was collected to study whole blood (WB) coagulation profiles. Thrombin generation (TG) was measured in WB and platelet poor plasma (PPP) of 18 patients with PDAC and 18 healthy individuals matched for age and sex. The capacity of platelets to release granules was measured in a time-dependent manner upon stimulation with a PAR1 receptor agonist in WB. Patients were followed for 6 months upon inclusion. The primary endpoint was the onset of thromboembolic events, both VTE and arterial thromboembolism (ATE). Results Patients with PDAC have an increased endogenous thrombin potential (ETP) in whole blood. This difference was not observed in PPP, indicating a procoagulant effect caused by blood cells. Furthermore, patients with PDAC have a prolonged lag time in whole blood, while the lag time in PPP was not different between patients and controls. Platelet and white blood cell counts (WBC) significantly correlated with the WB ETP and peak in patients with PDAC, which was not observed in healthy controls. Of the 18 PDAC patients, 4 developed a VTE (22%) and 1 an ATE (6%). A shorter lag time of WB-TG and an increased maximum capacity of platelets to release granules, at study inclusion, were associated with incident thromboembolic events. Conclusions Patients with PDAC have an imbalanced WB-TG profile. The lag time in WB-TG and the granule release capacity of platelets predict an increased incidence of thromboembolic events. Red blood cell and white blood cell abnormalities in PDAC are associated with this disturbance in thrombin generation. Platelets and white blood cells hence appear to be a driving force in the development of thrombosis in patients with PDAC. As such, measuring hemostasis in whole blood would improve the thrombosis risk estimation in PDAC patients.

Association of Antipsychotic Drugs with the Risk of Recurrent Venous Thromboembolism: A Retrospective Study of Data from a Japanese Inpatient Database.

Approximately a decade has passed since the addition of venous thromboembolism to the list of significant adverse reactions of antipsychotic drugs. However, only a few studies have investigated the relationship between antipsychotic use and venous thromboembolism in the Japanese population. We aimed to evaluate the risk of recurrent venous thromboembolism in users of antipsychotic drugs and update the evidence on venous thromboembolism in the Japanese population. A cross-sectional retrospective analysis of data from a large Japanese claims database, managed by Medical Data Vision Co. Ltd., was conducted. Adult patients who experienced venous thromboembolism between October 2014 and September 2018 in acute care hospitals were identified. The risk of recurrent venous thromboembolism was evaluated with logistic regression using demographic variables. The data of patients using antipsychotic drugs within specific therapeutic classes were also evaluated. We included 8960 patients (mean age, 69years; 59.2% female). Recurrent venous thromboembolism was observed in 686 patients (7.7%). The risk of recurrent venous thromboembolism was significantly higher in younger patients [<65years: reference; 65-74years: odds ratio (OR) 0.81, 95% confidence interval (CI) 0.66-0.99, p = 0.04; ≥75years: OR 0.77, 95% CI 0.64-0.94, p = 0.01], those with history of surgery (OR 1.39, 95% CI 1.18-1.65, p = 0.01), and anticoagulant users (OR 2.25, 95% CI 1.46-3.48, p = 0.01) and was significantly lower in the presence of comorbidities (OR 0.68, 95% CI 0.58-0.81, p< 0.01) and fractures (OR 0.49, 95% CI 0.26-0.94, p = 0.03). Long-term antipsychotic drug prescriptions (>14days) were associated with a higher risk of venous thromboembolism than short-term prescriptions (≤14days) (OR 1.56, 95% CI 1.04-2.34, p = 0.03). In patients with a history of venous thromboembolism, particular attention should be paid to recurrence in younger patients. If antipsychotic drugs are prescribed for >14days to patients with a history of venous thromboembolism, they should be administered carefully, guided by reported findings. Further evaluations using different databases or populations are required to generalize the findings of this study.

Predictive Efficacy of the Khorana Score in Black Patients: Retrospective Cohort Study

Background The Khorana score(KS) is a predictive score used to determine the risk of venous thromboembolism (VTE) in cancer(CA) patients(pts). According to the original study, a score of 1-2 was consistent with an intermediate risk(IR) for VTE (VTE risk(VTER)) of 1.8-2.0% at 2.5 months). A score of &amp;gt;3 was associated with a high risk(HR) of VTE (6.7-7.1% VTER at 2.5 months). Several studies have noted an increased risk of VTE in Black CA pts. The original KS study did not stratify pts based on race. We sought to determine if the Khorana score was appropriately predictive of VTE in Black CA pts at our institution, using pre-chemotherapy lab values to calculate the score. Methods Retrospective study. Inclusion: any CA between 01/01/2015-12/31/2021, aged 18-100 years. Exclusion: history of anticoagulation 6 months prior to CA diagnosis, history of chronic VTE, history of arterial thromboembolism. Follow-up period: 1 year post cancer diagnosis or until death if sooner. Discussion The population was composed of 233 patients. Black pts(AA) composed 39.9%; White pts(WP) composed 60.1%. Mean age of the population was 61.3 years (standard deviation (SD) 12.4). Male patients composed 49.8%. At the time of the study 39.9% were deceased; the mean duration from CA to death was 14.5 months (SD 15.0). Most common CA stage was stage IV (21.03%); breast cancer was most prevalent (15.9%). The median follow-up time was 12.0 months (IQR 7.9). VTE occurred in 39.9%; mean cancer-to-VTE duration was 4.4 months (SD 3.2). The mean cancer-to-VTE duration in AA was 4.5 months (SD 3.4); 4.3 months (SD 3.2) in WPs. The average Charlson comorbidity index(CCI) for the population was 3.3 (SD 2.9); there were no differences between groups when CCI was evaluated (Table 1). The population mean Khorana score was 1.3 (SD 1.2). The Khorana score for: AA was 1.4 (SD 1.1) and 1.3 (SD 1.2) in WPs. The average Khorana scores were: AA without VTE 1.4 (SD 1.1), AA with VTE 1.5 (SD 1.1), WP without VTE 1.1 (SD 1.1), WP with VTE 1.5 (SD 1.2). There were no differences between any of these average Khorana scores (Table 1). The average population Khorana score for VTE regardless of race was 1.5 (SD 1.2) and 1.3 (1.2) for patients without VTE; this was not a significant finding (p=0.130). The positive predictive value (PPV) of the KS was determined for each KS group by race (i.e., HR score &amp;gt;3, IR score 1-2, low risk(LR) score 0). AA: HR PPV 13%, IR PPV 31%, LR PPV 17%. WP: HR PPV 65%, IM PPV 54%, LR PPV 34%. These values were significantly different between AA and WP for all risk groups (p&amp;lt;0.001) except LR (p=0.11). Distant metastasis occurred in 22/233 (9.4%) of the total study population. More patients with VTE had distant metastasis (16/93, 17.2%) than patients without VTE (6/140, 4.3%); (OR: 4.641, 95% CI 3.7 -5.6; p=0.001). Conclusion Most patients developed VTE around 4 months following CA diagnosis. Our study shows that the KS may not be a good predictor of VTE in AA. While there was a stepwise increase in the PPV of the KS for VTE in WPs, such a pattern was not seen in AA. Pts with distant metastasis were 4.6 times more likely to have VTE.

Association of eGFR and Albuminuria with Venous Thromboembolism.

CKD has been implicated as a risk factor of venous thromboembolism, but the evidence is limited to relatively healthy populations. The objective of this study was to discern whether parameters of kidney function and damage are associated with the occurrence of venous thromboembolism after hospitalization. We conducted a retrospective study including 23,899 and 11,552 adult individuals hospitalized within Geisinger Health System and New York University (NYU) Langone Health from 2004 to 2019 and 2012 to 2022, respectively. A Poisson model was used to evaluate adjusted incidence rates of venous thromboembolism according to eGFR and albuminuria categories in each cohort. Cox proportional hazards models were used to analyze associations of eGFR and urinary albumin-to-creatinine ratio (UACR) with venous thromboembolism, and hazard ratios (HRs) were meta-analyzed across cohorts. Both lower eGFR and higher UACR were associated with higher risks of venous thromboembolism. In the Geisinger cohort, the incidence of venous thromboembolism after hospital discharge ranged from 10.7 (95% confidence interval [CI], 9.2 to 12.6) events per 1000 person-years in individuals in G1A1 (eGFR >90 ml/min per 1.73 m 2 and UACR <30 mg/g) to 27.7 (95% CI, 20.6 to 37.2) events per 1000 person-years in individuals with G4-5A3 (eGFR <30 ml/min per 1.73 m 2 and UACR >300 mg/g). A similar pattern was observed in the NYU cohort. Meta-analyses of the two cohorts showed that every 10 ml/min per 1.73 m 2 reduction in eGFR below 60 ml/min per 1.73 m 2 was associated with a 6% higher risk of venous thromboembolism (HR 1.06 [95% CI, 1.02 to 1.11], P = 0.01), and each two-fold higher UACR was associated with a 5% higher risk of venous thromboembolism (HR 1.05 [95% CI, 1.03 to 1.07], P < 0.001). Both eGFR and UACR were independently associated with higher risk of venous thromboembolism after hospitalization. The incidence rate was higher with greater severity of CKD. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_12_14_CJN0000000000000352.mp3.

Cardiovascular events and venous thromboembolism after primary malignant or non-malignant brain tumour diagnosis: a population matched cohort study in Wales (United Kingdom)

BackgroundElevated standardised mortality ratio of cardiovascular diseases (CVD) in patients with brain tumours may result from differences in the CVD incidences and cardiovascular risk factors. We compared the risk of CVD among patients with a primary malignant or non-malignant brain tumour to a matched general population cohort, accounting for other co-morbidities.MethodsUsing data from the Secured Anonymised Information Linkage (SAIL) Databank in Wales (United Kingdom), we identified all adults aged ≥ 18 years in the primary care database with first diagnosis of malignant or non-malignant brain tumour identified in the cancer registry in 2000–2014 and a matched cohort (case-to-control ratio 1:5) by age, sex and primary care provider from the general population without any cancer diagnosis. Outcomes included fatal and non-fatal major vascular events (stroke, ischaemic heart disease, aortic and peripheral vascular diseases) and venous thromboembolism (VTE). We used multivariable Cox models adjusted for clinical risk factors to compare risks, stratified by tumour behaviour (malignant or non-malignant) and follow-up period.ResultsThere were 2869 and 3931 people diagnosed with malignant or non-malignant brain tumours, respectively, between 2000 and 2014 in Wales. They were matched to 33,785 controls. Within the first year of tumour diagnosis, malignant tumour was associated with a higher risk of VTE (hazard ratio [HR] 21.58, 95% confidence interval 16.12–28.88) and stroke (HR 3.32, 2.44–4.53). After the first year, the risks of VTE (HR 2.20, 1.52–3.18) and stroke (HR 1.45, 1.00–2.10) remained higher than controls. Patients with non-malignant tumours had higher risks of VTE (HR 3.72, 2.73–5.06), stroke (HR 4.06, 3.35–4.93) and aortic and peripheral arterial disease (HR 2.09, 1.26–3.48) within the first year of diagnosis compared with their controls.ConclusionsThe elevated CVD and VTE risks suggested risk reduction may be a strategy to improve life quality and survival in people with a brain tumour.

EPID-08. CLINICAL AND MOLECULAR DETERMINANTS OF BLEEDING-RELATED ADVERSE OUTCOMES IN HIGH-GRADE GLIOMA

Abstract Cancer is an independent risk factor for the development of venous thromboembolism (VTE) however patients with high-grade glioma (HGG) including glioblastoma (GBM) are at a particularly high risk of VTE with an incidence up to 20- 30% per year. Patients are often placed on anticoagulation to reduce the risk of VTE. However, patients with primary brain tumors such as HGG are at increased risk for intracerebral hemorrhage (ICH) even without the administration of anticoagulation. The combination of risk factors for ICH with anticoagulation and HGG complicates decision-making. Currently it is not known which of the direct oral anticoagulants (DOACs) are safest for patients with HGG in terms of adverse bleeding-related outcomes such as ICH. Furthermore, a deeper understanding of the clinical and molecular determinants of bleeding-related adverse outcomes in HGG is not fully characterized. In this study, we gathered data on patients with HGG from two Ascension Seton Hospitals in the Austin metro area from July 1, 2017 through June 30, 2022. We identified 76 pathology-confirmed patients with HGG. Patients who were on rivaroxaban (3/7 (43%), p=.022) had a statistically significant association with more bleeding-related adverse events compared to those on apixaban (0/12 (0%)) or enoxaparin (0/5 (0%)) even though the groups were similar in terms of their characteristics including total time on the respective anticoagulation. Patients on anticoagulation vs those never on anticoagulation did not differ in terms of their studied demographic and clinical characteristics. Intriguingly, logistic regression analysis revealed that patients harboring isocitrate dehydrogenase (IDH) mutations had a statistically significant association with more adverse bleeding-related events even when controlling for other relevant factors (Odds Ratio compared to reference GBM: 115.7; p=.014). This study offers insights into our understanding of relevant factors associated with worse bleeding-related adverse outcomes such as ICH in patients with HGG.

NCOG-17. RETROSPECTIVE REVIEW OF THE TREATMENT OF VENOUS THROMBOEMBOLISM IN GLIOBLASTOMA PATIENTS RECEIVING BEVACIZUMAB

Abstract Patients with malignant gliomas have an inherently high risk of venous thromboembolism (VTE).1 Bevacizumab is an anti-vascular endothelial growth factor (VEGF) monoclonal antibody commonly used in the treatment of recurrent high-grade gliomas and is known to increase the risk of VTE as well as intracranial hemorrhage.2 Anticoagulation (AC) for VTE also increases the risk intracranial hemorrhage in patients with malignant brain tumors.3 This makes the treatment of VTE in patients with GBM receiving bevacizumab therapy particularly challenging. Here we completed a single center retrospective chart review of patients with glioblastoma (GBM) treated concurrently with anticoagulation for VTE and bevacizumab therapy. The purpose of this review was to assess the safety of concurrent use of these therapies and to note any statistically significant difference in the incidence of hemorrhagic complications between patients treated with anticoagulation at therapeutic versus prophylactic dosing. METHODS: 144 patients with a diagnosis of high-grade glioma and were treated at UCI from 1/1/2019 through 1/1/2022 were screened for the study. 13 GBM patients on treatment with bevacizumab and concurrent anticoagulation were included. Clinical records of these patients were reviewed for the incidence of intracranial hemorrhage or any clinically significant bleeding. RESULTS: The incidence of ICH in GBM patients on concurrent therapy with bevacizumab and anticoagulation was 7.7% and the incidence of other minor bleeding complications was 7.7%. ICH and other minor bleeding was exclusively seen in patients on therapeutic anticoagulant dosing. No bleeding complications were noted in patients on prophylactic AC dosing. CONCLUSION: There is a risk of ICH in patients receiving both bevacizumab and anticoagulation, however compared to historical data, the incidence reported in our study is less than the incidence of ICH in GBM patients on anticoagulation alone. Our study suggests that it is relatively safe to treat patients with these therapies simultaneously.

Season of delivery and risk of venous thromboembolism during hospitalization among pregnant women.

Seasons were found to be related to the occurrences of venous thromboembolism (VTE) in hospitalized patients. No previous study has explored whether seasons were associated with VTE risk in pregnant women. This study aimed to investigate the relationships between the season of delivery and VTE risk during hospitalization among pregnant women. This is a multi-center retrospective cohort study of pregnant women. Participants were those who delivered at seven designated sites in Hubei Province, China, during the period from January 2017 to December 2022. They were categorized according to their season/month of delivery. Information on new-onset VTE during hospitalization was followed. Approximately 0.28% (104/37,778) of the pregnant women developed new-onset VTE during hospitalization for delivery. After adjustment, compared with participants in the spring group, participants in the summer, autumn, and winter groups had an increased risk of VTE during hospitalization. The ORs were 2.59 [1.30, 5.15], 2.83 [1.43, 5.60], and 2.35 [1.17, 4.75] for the summer, autumn, and winter groups, respectively. Pregnant women in the combined group (summer + autumn + winter) had an increased risk of VTE during hospitalization than those in the spring group (OR, 2.59 [1.39, 4.85]). By restricting the analyses among pregnant women without in vitro fertilization, gestational diabetes mellitus, and preterm, the results still remained robust. Compared with participants who delivered in March, April, and May, participants who delivered in June, July, September, November, December, and February had a higher risk of VTE during hospitalization. This study demonstrated that pregnant women who delivered in summer, autumn, and winter had an increased VTE risk during hospitalization compared with those who delivered in spring.

Development and Validation of a Modified Khorana Score for Predicting Venous Thromboembolism in Newly Diagnosed Stage IV Lung Cancer.

We aimed to establish an effective model to identify metastatic lung cancer patients at high risk of venous thromboembolism (VTE). Patients diagnosed with stage IV lung cancer from January 2011 to June 2019 were included in the development cohort; those recruited from July 2019 to June 2021 were included in the validation cohort. Univariable and multivariable analyses determined the risk factors for VTE. Then we assessed the value for predicting VTE of the Khorana score and modified Khorana score in these two cohorts; 575 patients were included in the development cohort, and 202 patients in the validation cohort. Adenocarcinoma, D-dimer, and the Khorana score were independent risk factors for VTE. In the development cohort, the area under the receiver operating characteristic curve (AUC) of the Khorana score in patients with newly diagnosed stage IV lung cancer was 0.598 (95% CI, 0.512-0.684). The AUC of the modified Khorana score was 0.747 (95% CI, 0.689-0.805). The difference was statistically significant (P <.001). The AUC of the modified Khorana score in the validation cohort was 0.763 (95% CI, 0.661-0.865). The modified Khorana score is more able to accurately predict VTE in patients with newly diagnosed stage IV lung cancer than the Khorana score.

Venous Thromboembolism and Estrogen-Containing Gender-Affirming Hormone Therapy.

Gender-affirming therapy involves the use of hormones to develop the physical characteristics of the identified gender and suppressing endogenous sex hormone production. Venous thromboembolism (VTE) is a known risk of exogenous estrogen therapy, and while evidence of VTE risk among transgender women using modern gender-affirming hormone therapy (GAHT) is still emerging, it is thought to affect up to 5% of transgender women. Historically, GAHT was associated with a high risk of VTE; however, modern preparations are less thrombogenic mainly due to significantly lower doses used as well as different preparations. This review presents the available literature regarding the following four topics: (1) risk of VTE among transgender women receiving estradiol GAHT, (2) how the route of administration of estradiol affects the VTE risk, (3) perioperative management of GAHT, (4) VTE risk among adolescents on GAHT. There is a need for large, longitudinal studies of transgender women using GAHT to further characterize VTE risk and how this is affected by factors such as patient age, duration of GAHT use, tobacco use, body mass index, and comorbidities. Future studies in these areas could inform the development of clinical guidelines to improve the care of transgender people.

A Transformer Natural Language Processing Algorithm for Cancer Associated Thrombosis Phenotype

Introduction: Cancer patients have high risk of venous thromboembolism (VTE). The ability to accurately capture VTE outcome in large electronic health record (EHR) is critical for both surveillance and risk stratification. We previously published a rule-based natural language processing (NLP) algorithm that relied on radiology reports alone with a precision (positive predictive value) of 89% and recall (sensitivity) of 69-78% (sTable 5 PMID36626707). The low recall metric was expected as VTE diagnosis that occur at outside hospital would not be captured by radiology reports. In the current study, we aimed to assess the performance of a machine learning NLP algorithm using both radiology and medical notes to detect cancer associated VTE longitudinally in a large cancer cohort. Methods: VTEwasdefined as symptomatic or incidental pulmonary embolism, lower or upper extremity deep vein thrombosis. Unusual thrombosis such as splanchnic vein thrombosis (mostly tumor thrombi) was classified as negative. Figure 1 details the study design: i) patient selection, ii) pre-annotation filtering, iii) gold standard annotation, iv) transformer model development. From a cohort of 9,769 patients with active cancer receiving first-line systemic therapy, we first pre-filtered all clinic progress notes, discharge summaries, and radiology reports to exclude sections with little clinical relevance (e.g. review of systems, physical exam), while maintaining sections with high clinical value (e.g. history of present illness, assessment/plan, hospital problems/course). Then, we kept notes with VTE keyword stems (e.g. VTE, PE, DVT, thromb, embol, clot, filling defect, phlebitis). We selected 808 patients with at least 1 keyword to determine the gold standard VTE date and location through independent chart review process. This cohort was randomly split into a training and testing cohort at an 7:1 ratio. In the training cohort (n=708), we further annotated all keyword-containing phrases within 30 days (d) from VTE date and from index date until 180d if no VTE (n=~2,000). The ~800 positive and ~1,200 negative keyword-containing phrases were used to train ClinicalBERT (bidirectional encoder representation transformer) large language model through split-sample cross validation to finetune the loss function and to determine the prediction threshold. Finally, we applied the entire trained model package to every available notes/reports (n=~2300) in the test cohort (n=100) to assess if the first positively predicted date would correlate with the gold standard VTE date. Results: The finetuned ClinicalBERT modelachieved 98% precision and 98% recall on the patient level in the training cohort (n=708). When applied on the 100-patient test cohort, the model accurately predicted first VTE events in 50/54 patients (93% precision) and captured 50/54 of patients with VTE (93% recall sensitivity) (Table 1). Most of the tumor thrombi and superficial venous thrombi were correctly classified as negative. The false positives were related to unusual sentences with both positive and negative findings such as “Thrombosis surrounding the left brachial catheter in basilic vein,” “CT chest with PE was done,” “Lovenox was initiated for UE DVT, but this was port thrombosis in the basilic vein.” The false negatives were related to isolated VTE diagnosis close to death or loss to follow-up. Notably, the precision and recall tradeoff can be further finetuned by changing the minimum number of positively predicted notes from the NLP. Conclusion: In conclusion, we successfully developed and tested a transformer NLP model to detect cancer associated VTE longitudinally using a combination of clinical notes and radiology reports that achieved a precision of 93% and recall of 93%. This represented an improvement over our original algorithm with radiology report alone. Further validation of the model in external cohorts and finetuning through federated or transferred learning are ongoing to ensure model generalizability and usability.

Circulating Tumor DNA and Risk of Venous Thromboembolism in Locally Advanced Rectal Cancer

Venous thromboembolism (VTE) is a common complication in cancer patients, which negatively affects treatment delivery and, consequently, prognosis. The pathophysiology of cancer-associated thrombosis (CAT) is extremely complex, relying on cytokine release in response to interactions between tumor cells and macrophages, thus leading to endothelial damage and activation of coagulation. Several risk factors may contribute to VTE risk, including tumor types, advanced stage, and anti-cancer treatments. Anti-angiogenic agents or combination of systemic chemotherapy and concomitant radiotherapy (CT-RT), for instance, are well-established risk factors across different malignancies. Colorectal cancer (CRC) is not listed as a high-risk VTE tumor according to pivotal risk assessment models, although retrospective studies showed a VTE rate of around 20%. Consequently, considering the high prevalence of the disease, VTE in CRC represents a main burden in terms of morbidity, increased healthcare costs, and mortality. Rectal cancer (RC) comprises approximately 30% of all CRC. The treatment of locally advanced disease (LARC) consists of a multimodal approach which includes chemotherapy, radiotherapy, and surgery. In the context of CRC management, circulating tumor DNA (ctDNA) is a fast-growing tool able to detect minimal residual disease, useful for improving patients' stratification and prognosis. Moreover, its determination at the time of diagnosis may represent a surrogate of tumor burden, potentially increasing the risk of VTE compared to ctDNA negative patients. Due to the paucity of prospective data of VTE in LARC, the aim of this analysis is to describe the rate of VTE and the potential association between ctDNA levels at baseline and VTE occurrence. We conducted a prospective observational study enrolling patients with LARC managed with neoadjuvant CT-RT (capecitabine 1650 mg/m2 concomitant with 50,4 Gy pelvic long course radiotherapy), surgery, plus/minus adjuvant chemotherapy at European Institute of Oncology (IEO) between November 2014 and November 2019. Blood samples for ctDNA were obtained at pre-planned timepoints: baseline (T0), end of CT-RT (T1), after surgery (T2), end of adjuvant chemotherapy (T3). ctDNA was extracted from plasma and mutations detected on tumor biopsy (KRAS, NRAS, BRAF, PIK3CA) were evaluated on ctDNA. Among other clinical information, VTE events were collected, including pulmonary embolism (PE), deep vein thrombosis (DVT) and visceral venous thrombosis (VVT). VTE was counted when occurred after or whitin 30 days before LARC diagnosis. The ctDNA value, defined as variant allele frequency (VAF) in a targeted mutation, was analyzed for correlation with clinical outcomes and VTE events. Median baseline ctDNA value was set as threshold to subdivide patients in VAF high and VAF low. We enrolled 111 patients. Sixty-one (55%) patients harboring tumoral tissue mutations underwent liquid biopsy. KRAS mutation was the most frequent one (42%), followed by NRAS (7%) and PIK3CA (5%). Fifty-one patients (83%) had a clinical node positive disease. Baseline Khorana Score (KS) was 0 in 54 patients (88%) and 1 in 7. Median ctDNA value at T0 was 0.11 ng/2ml (range: 0.00 - 17.40). After a median follow up of 82 months, 9 VTE events (15%) were diagnosed, 4 PE, 3 DVT and 2 VVT. The median time from diagnosis to VTE event was 14 months (IQR 6 - 51). VTE occurrence was associated with VAF high at baseline, even though not statistically significant (Hazard Ratio [HR]: 2.85; 95% CI: 0.71-11.4, p value = 0.14). Looking specifically at KRAS mutant patients, 6 VTE events were observed, all experienced by VAF high patients (HR not estimable, p value = 0.001). Considering the overall population, VTE rate was 14% and no statistical differences were observed for VTE development according to mutational profile. In our prospective study on LARC patients, VTE was associated with high levels of ctDNA at diagnosis, although not statistically significant. However, the association was significant in KRAS mutant tumors, which may represent a subset of patients with higher risk of thromboembolic complications. Prospective translational studies using deeper molecular techniques and wider populations are required to define the role of ctDNA as additional predictive tool to stratify VTE risk in cancer patients.

Development of a Combined Risk Assessment Model for Venous Thromboembolism and Bleeding in Hematopoietic Stem Cell Transplantation Patients

Background: Venous thromboembolism (VTE) and bleeding are common complications amongst allogeneic and autologous hematopoietic stem cell transplant (HSCT) patients. Balancing risk of bleeding and thrombosis in this population is particularly challenging as HSCT patients are concurrently pancytopenic and coagulopathic. However, risk factors for bleeding and thrombosis in HSCT patients are understudied. We aimed to derive a combined bleeding and VTE risk assessment tool to be used in the immediate post-transplant period (90 days). Methods: We conducted a retrospective cohort study of adult patients who underwent allogeneic or autologous HSCT between January 1, 2011 and December 31, 2021 at a tertiary care centre in Canada. The risk models patients were followed from transplant until occurrence of the event of interest with last follow up at Day 90 post-transplant, or death. Primary outcome for VTE was the occurrence of a confirmed thrombosis including proximal upper and lower extremity deep vein thrombosis, pulmonary embolism, or thrombosis of unusual sites, including cerebral and splanchnic. Primary outcome for bleeding was the occurrence of a major or clinically significant non-major bleeding event, not related to anticoagulation, as per the definition of the International Society of Thrombosis and Hemostasis. Group characteristics were compared using chi-square, Fisher's exact, or Student's T-tests as appropriate. Potential predictors for VTE and bleed amongst our patients were evaluated using single variable logistic regression and confirmed with multiple variable logistic regression with forward selection. For continuous variables, optimal cut-off points were estimated using ROC curves. Final VTE and bleed risk scores were derived based on weighted variables and compared using Cox regression with non-parametric bootstrapping used for internal validation. Results: A total of 476 patients (317 autologous, 159 allogeneic) were included. 47 patients (9.8%) suffered from VTE, and 32 patients (6.7%) suffered from bleed unrelated to anticoagulation within 90 days post-HSCT. A VTE risk assessment tool was derived, and internally validated, and it included: second central venous catheter insertion (due to complications from first central line) (2 points), and previous cancer treatment with steroids (1 point). The overall cumulative incidence of VTE was 31.8% in the high-risk group (&amp;gt;2 points) versus 7.6% in the low-risk group (0-1 points). The high-risk group was associated with higher mortality at 90 days (15.9% versus 3.2%, p &amp;lt;0.001; Figure 1). A bleeding risk assessment tool was also derived, and internally validated, and it included: baseline (day 0 of transplant) platelet count of &amp;lt;90 (1 point), and baseline hemoglobin of &amp;lt;96 (1 point). The overall cumulative incidence of bleed was 17.2% in the high-risk group (2 points), versus 4.3% in the low-risk group (0-1 points). The high-risk group was associated with higher mortality at 90 days (12.6% versus 2.6%, p&amp;lt;0.001). Amongst the low-risk bleed group, overall cumulative incidence of VTE was 10.03%, with 31.03% in the high-risk VTE group versus 8.33% in the low-risk VTE group (p&amp;lt;0.001). The positive VTE group was associated with higher mortality at 90 days (10.26% versus 1.72%, p=0.001; Figure 2). Amongst the high-risk bleed group, overall cumulative incidence of VTE was 9.19%, with 33.33% in the high-risk VTE group, versus 4.17% in the low-risk VTE group (p&amp;lt;0.001). The positive VTE group was associated with higher mortality at 90 days (37.5% versus 10.13%, p=0.026). Conclusion: We derived a predictive score, VTE and Bleeding in Marrow Transplant (VBMT) - risk score, for both VTE and bleeding in the immediate post-transplant period (90 days), to be used in conjunction with other criteria for bleeding and thrombosis. Amongst the low-risk bleed patients, we recommend strong consideration of chemical VTE prophylaxis, especially amongst the high-risk VTE group. These risk assessment models will help stratify patients based on bleed and thrombosis risk, and ultimately help guide VTE prophylaxis and surveillance strategies amongst HSCT patients.

Development and external validation of a prediction model for venous thromboembolism in systemic lupus erythematosus

ObjectivePatients with systemic lupus erythematosus (SLE) have an increased risk of venous thromboembolism (VTE). We conducted this study to develop a risk score algorithm for VTE in patients with SLE...

Serum PLA2R antibody as a predictive biomarker for venous thromboembolism risk in primary membranous nephropathy

BackgroundPatients with nephrotic syndrome are at high risk of venous thromboembolism (VTE), especially for primary membranous nephropathy (PMN). The phospholipase A2 receptor (PLA2R) is a marker of primary membranous nephropathy activity. This study investigated the predictive value of PLA2R antibodies in PMN for VTE. MethodsIn this retrospective study, we included 97 PMN patients and evaluated the predictive value of serum PLA2R antibodies for VTE risk. Lower extremity venous ultrasound, renal vein ultrasound, or spiral computed tomography pulmonary arteriography were used to assess VTE events. Serum anti-PLA2R antibodies were detected by enzyme-linked immunosorbent assay (ELISA). The risk of VTE was stratified according to serum albumin levels. ResultsTwenty PMN patients (21%) had thromboembolic events. Eight (15%) of patients with serum albumin >25g/l developed VTE, 6 of whom were positive for serum PLA2R antibodies. Positive serum PLA2R antibodies were significantly associated with VTE events in patients with serum albumin >25g/l (p=0.01). Age, sex, blood creatinine, serum albumin, and 24-h urine protein levels were not statistically different between the two groups. Kaplan–Meier analysis using the log-rank test revealed anti-PLA2R positive membranous nephropathy patients had more probability of VTE events than anti-PLA2R negative patients. Univariate Cox proportional hazards analysis revealed that lnPLA2R-Ab is an unfavorable predictor for VTE events in patients with serum albumin >25g/l (hazard ratio (HR) 2.1, p=0.01). ConclusionsThe PLA2R antibody was a risk predictor for thromboembolic events in patients with primary membranous nephropathy with serum albumin >25g/l.