Venous Thromboembolism Risk Stratification Research Articles

Association between epidermal growth factor receptor-tyrosine kinase inhibitors and venous thromboembolism among older patients with advanced non-small cell lung cancer.

Venous thromboembolism (VTE) risk is higher among patients with non-small cell lung cancer (NSCLC) and specific subgroups, including the elderly, but little is known about the VTE risk of different generations of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) and whether the risk differs by demographic characteristics. This study aims to compare the risk of VTE (deep venous thromboembolism [DVT]; pulmonary embolism [PE]) between a third-generation EGFR-TKI and first/second-generation EGFR-TKIs and stratify VTE risk by sex, age, and race/ethnicity in third-generation EGFR-TKI users. Via the 2006-2019 Surveillance, Epidemiology, and End Results-Medicare database, this retrospective cohort study included older patients (aged ≥65 years) with advanced NSCLC who initiated on a third-generation EGFR-TKI (n=493) and first/second-generation EGFR-TKIs (n=1036). We estimated the hazard ratio (HR) and its 95% confidence interval (95% CI) with the Cox proportional hazards model. A third-generation EGFR-TKI had a significantly higher VTE risk than first/second-generation EGFR-TKIs (HR, 1.26 [95% CI, 1.01-1.57]; p=.037), with an elevated risk in males (HR, 2.16 [95% CI, 1.47-3.19]; p<.001), patients aged ≥75 years (HR, 1.38 [95% CI, 1.04-1.83]; p=.026), and non-Hispanic Whites (HR, 1.46 [95% CI, 1.10-1.95]; p=.010). Males consistently showed a significantly higher risk of DVT (HR, 2.49 [95% CI, 1.29-4.80]; p=.007) and PE (HR, 2.00 [95% CI, 1.29-3.11]; p=.002). A significantly higher risk of DVT (HR, 1.54 [95% CI, 1.00-2.37]; p=.050) and PE (HR, 1.47 [95% CI, 1.06-2.05]; p=.021) was shown in patients aged ≥75 years and non-Hispanic Whites, respectively. Among third-generation EGFR-TKI users, non-Hispanic Whites had a significantly higher risk of VTE (HR, 2.04 [95% CI, 1.03-4.02]; p=.041) and PE (HR, 2.88 [95% CI, 1.24-6.70]; p=.014) than non-Hispanic Asian/Pacific Islanders. Close monitoring of VTE events in high-risk patients is essential to promote early diagnosis and treatment.

Risk profile and thromboprophylaxis practices among patients undergoing laparotomy at Moi teaching and referral hospital

Background: Venous thromboembolism (VTE) significantly causes hospital mortality worldwide, with abdominal surgery a risk factor. Venous thromboprophylaxis can reduce VTE risk, but has adverse effects. Local research on risk profile and practice helps individualize thromboprophylaxis and develop local protocols. Methods: A prospective study was conducted at Moi teaching and referral hospital (MTRH) on adult laparotomy patients. The minimal sample size was 325 patients, using consecutive sampling. DVT was assessed using Well's score perioperatively, 2 weeks and 4 weeks postoperatively. A lower limb Doppler ultrasonography was performed on patients with a score of 2 or greater to rule out DVT. Results: The mean age of study participants was 38 years, with a 1.5:1 male-to-female ratio. Infection in the abdomen was the main reason for laparotomy. All procedures were open, and 75.4% of individuals had high or moderate VTE risk. Within 72 hours, 82.7% of patients were mobilized. Chemoprophylaxis was limited to enoxaparin post-op. Enoxaparin duration was unstandardized, and MTRH VTE risk categorization chart use was not reported. 3% of individuals received chemoprophylaxis against ACCP guidelines and 12% received enoxaparin despite contraindications. Only 13% and 24% of intermediate and high-risk patients got chemoprophylaxis. No mechanical prophylaxis was used. Symptomatic DVT was 6.8%. Advanced age, Caprini score, and enoxaparin prescription increased symptomatic DVT risk. Conclusions: Despite increased laparotomies for intra-abdominal infection and middle-aged patients, VTE is common in MTRH patients. Poor VTE risk stratification and MTRH protocol failure led to improper thromboprophylaxis. Prescribers should employ MTRH VTE regimen for proper prophylaxis. Providing prescribers with thromboprophylaxis choices to customize prescriptions.

What Constitutes High Risk for Venous Thromboembolism? Comparing Approaches to Determining an Appropriate Threshold.

Guidelines recommend pharmacological venous thromboembolism (VTE) prophylaxis only for high-risk patients, but the probability of VTE considered "high-risk" is not specified. Our objective was to define an appropriate probability threshold (or range) for VTE risk stratification and corresponding prophylaxis in medical inpatients. Patients were adults admitted to any of 10 Cleveland Clinic Health System hospitals between December 2020 and August 2021 (N = 41,036). Hospital medicine physicians and internal medicine residents from included hospitals were surveyed between June and November 2023 (N = 214). We compared five approaches to determining a threshold: decision analysis, maximizing the sensitivity and specificity of a logistic regression model, deriving a probability from a point-based model, surveying physicians' understanding of VTE risk, and deriving a probability from physician behavior. For each approach, we determined the probability threshold above which a patient would be considered high-risk for VTE. We applied each threshold to the Cleveland Clinic VTE risk assessment model (CCM) and calculated the percentage of the 41,036 patients in our cohort who would be considered eligible for prophylaxis due to their high-risk status. We compared these hypothetical prophylaxis rates with physicians' observed prophylaxis rates. The different approaches yielded thresholds ranging from 0.3% to 5.4%, corresponding inversely with hypothetical prophylaxis rates of 0.2% to 75%. Multiple thresholds clustered between 0.52% to 0.55%, suggesting an average hypothetical prophylaxis rate of approximately 30%, whereas physicians' observed prophylaxis rates ranged from 48% to 76%. Multiple approaches to determining a probability threshold for VTE prophylaxis converged to suggest an optimal threshold of approximately 0.5%. Other approaches yielded extreme thresholds that are unrealistic for clinical practice. Physicians prescribed prophylaxis much more frequently than the suggested rate of 30%, indicating opportunity to reduce unnecessary prophylaxis. To aid in these efforts, guidelines should explicitly quantify high-risk.

The Association of Abdominoplasty with Breast Reduction (Mommy Makeover): Experience in An African University Hospital

Background: The popularity of breast reduction and abdominoplasty has significantly increased over the years, according to statistics from the American Society of Plastic Surgeons 2022. As a result, the Mommy Makeover, a procedure combining breast surgery and abdominoplasty, is not uncommon. Patients and Methods: A retrospective descriptive study was conducted over a four-year period within the Plastic and Aesthetic Surgery Department of the IBN SINA University Hospital, Rabat, Morocco. Results: Five cases of Mommy Makeover were operated on within the Plastic and Aesthetic Surgery Department of the IBN SINA University Hospital, Rabat, Morocco. One case was addressed two years after bariatric surgery. The procedure combined breast reduction with the superior-internal pedicle technique with Wise’s pattern and abdominoplasty. No major complications were observed. Discussion: Since the introduction of abdominoplasties combined with breast surgery, several concerns have been associated with this combination. Venous thromboembolism is the most commonly discussed consequence in combined plastic surgery procedures. The risk of venous thromboembolism is not elevated when abdominoplasty and breast reduction are combined. The study emphasizes the importance of careful patient selection and attentive venous thromboembolism prevention. It assesses the validity of the Davison-Caprini framework for venous thromboembolism risk stratification and prophylaxis in plastic surgery. Other measures to prevent complications were cited in the literature and followed by our operating team. Conclusion: With the help of a simple risk stratification tool that takes into account diabetes, age, BMI, and ASA status, we can guarantee favorable results for women who may want combined surgery.

DNA liquid biopsy-based prediction of cancer-associated venous thromboembolism

Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying high-risk patients for prophylactic anticoagulation is challenging and adds to clinician burden. Circulating tumor DNA (ctDNA) sequencing assays (‘liquid biopsies’) are widely implemented, but their utility for VTE prognostication is unknown. Here we analyzed three plasma sequencing cohorts: a pan-cancer discovery cohort of 4,141 patients with non-small cell lung cancer (NSCLC) or breast, pancreatic and other cancers; a prospective validation cohort consisting of 1,426 patients with the same cancer types; and an international generalizability cohort of 463 patients with advanced NSCLC. ctDNA detection was associated with VTE independent of clinical and radiographic features. A machine learning model trained on liquid biopsy data outperformed previous risk scores (discovery, validation and generalizability c-indices 0.74, 0.73 and 0.67, respectively, versus 0.57, 0.61 and 0.54 for the Khorana score). In real-world data, anticoagulation was associated with lower VTE rates if ctDNA was detected (n = 2,522, adjusted hazard ratio (HR) = 0.50, 95% confidence interval (CI): 0.30–0.81); ctDNA− patients (n = 1,619) did not benefit from anticoagulation (adjusted HR = 0.89, 95% CI: 0.40–2.0). These results provide preliminary evidence that liquid biopsies may improve VTE risk stratification in addition to clinical parameters. Interventional, randomized prospective studies are needed to confirm the clinical utility of liquid biopsies for guiding anticoagulation in patients with cancer.

Best Practices for Optimizing Patients Undergoing Surgical Procedures to Prevent Postoperative Venous Thromboembolism: A Quality Improvement Project.

Introduction Current studies suggest that both chemical and mechanical venous thromboembolism (VTE) prophylaxis is underused, which is concerning due to the potential lethality of VTEs. The Caprini risk score is a preoperative VTE risk assessment that determines a patient's risk of enduring a VTE. The objective of this study was to examine postoperative cases of VTE to determine if accurate VTE risk stratification was performed and whether appropriateVTE prophylaxis was administered. Methods A retrospective analysis was conducted on 23 reported cases of VTE that occurred at a Central Florida hospitalfrom April 1, 2021, to March 31, 2022. Relevant demographic and medical information was gathered from each patient chart to calculate an individual Caprini risk score and determine the type of chemical VTE prophylaxis that was received. Results Out of 23 reported cases of VTE in surgical patients, 17 were ultimately determined to have suffered VTE associated with their hospitalization and surgery. Thirteen out of 17 (76%) received appropriate perioperative chemical deep vein thrombosis (DVT) prophylaxis based on the calculated Caprini risk score and corresponding recommendations. Four out of 17 (24%) were determined to have received insufficient perioperative chemical DVT prophylaxis. Conclusion Consistent utilization of a DVT/pulmonary embolism (PE) risk stratification tool, such as the Caprini risk score calculator, is essential in the prevention of postoperative VTE. Hospitalscan improve the utilization of such a tool and thereby reduce the number of embolic events by making it more visible and accessible to the overseeing provider in the electronic medical record (EMR).

Higher incidence of venous thromboembolism associated with increasing lines of treatment in heavily treated ovarian cancer patients

ObjectiveOvarian cancer is associated with a high rate of venous thromboembolism. Our objective is to report the incidence of venous thromboembolism in recurrent ovarian cancer, assess the impact on morbidity...

Risk Assessment Models for Venous Thromboembolism in Medical Inpatients

Thromboprophylaxis is recommended for medical inpatients at risk of venous thromboembolism (VTE). Risk assessment models (RAMs) have been developed to stratify VTE risk, but a prospective head-to-head comparison of validated RAMs is lacking. To prospectively validate an easy-to-use RAM, the simplified Geneva score, and compare its prognostic performance with previously validated RAMs. This prospective cohort study was conducted from June 18, 2020, to January 4, 2022, with a 90-day follow-up. A total of 4205 consecutive adults admitted to the general internal medicine departments of 3 Swiss university hospitals for hospitalization for more than 24 hours due to acute illness were screened for eligibility; 1352 without therapeutic anticoagulation were included. At admission, items of 4 RAMs (ie, the simplified and original Geneva score, the Padua score, and the IMPROVE [International Medical Prevention Registry on Venous Thromboembolism] score) were collected. Patients were stratified into high and low VTE risk groups according to each RAM. Symptomatic VTE within 90 days. Of 1352 medical inpatients (median age, 67 years [IQR, 54-77 years]; 762 men [55.4%]), 28 (2.1%) experienced VTE. Based on the simplified Geneva score, 854 patients (63.2%) were classified as high risk, with a 90-day VTE risk of 2.6% (n = 22; 95% CI, 1.7%-3.9%), and 498 patients (36.8%) were classified as low risk, with a 90-day VTE risk of 1.2% (n = 6; 95% CI, 0.6%-2.6%). Sensitivity of the simplified Geneva score was 78.6% (95% CI, 60.5%-89.8%) and specificity was 37.2% (95% CI, 34.6%-39.8%); the positive likelihood ratio of the simplified Geneva score was 1.25 (95% CI, 1.03-1.52) and the negative likelihood ratio was 0.58 (95% CI, 0.28-1.18). In head-to-head comparisons, sensitivity was highest for the original Geneva score (82.1%; 95% CI, 64.4%-92.1%), while specificity was highest for the IMPROVE score (70.4%; 95% CI, 67.9%-72.8%). After adjusting the VTE risk for thromboprophylaxis use and site, there was no significant difference between the high-risk and low-risk groups based on the simplified Geneva score (subhazard ratio, 2.04 [95% CI, 0.83-5.05]; P = .12) and other RAMs. Discriminative performance was poor for all RAMs, with an area under the receiver operating characteristic curve ranging from 53.8% (95% CI, 51.1%-56.5%) for the original Geneva score to 58.1% (95% CI, 55.4%-60.7%) for the simplified Geneva score. This head-to-head comparison of validated RAMs found suboptimal accuracy and prognostic performance of the simplified Geneva score and other RAMs to predict hospital-acquired VTE in medical inpatients. Clinical usefulness of existing RAMs is questionable, highlighting the need for more accurate VTE prediction strategies.

Comparison of the PADUA and IMPROVE scores in assessing venous thromboembolism risk in 42,257 medical inpatients in China.

Venous thromboembolism (VTE) is a major contributor to hospital mortality and disability-adjusted life-year (DALY) loss. Multiple guidelines recommend using the Padua or IMPROVE scores to stratify VTE risk in hospitalized medical patients. However, the IMPROVE score is not recommended in Chinese guidelines, and there is very little evaluation of its clinical application and effectiveness in the Chinese population. The objective of this study is to compare the efficacy of the Padua and IMPROVE scoring models for assessing VTE risk in Chinese medical inpatients. We conducted a retrospective analysis of the clinical characteristics and thrombotic risk of 42,257 medical inpatients at a tertiary hospital in Guangdong, China, between 2021 and 2022. Logistic regression was used to assess thrombotic risk factors. The Receiver Operating Characteristic (ROC) curves, Area Under the Curve (AUC), sensitivity, and specificity were employed to evaluate the performance of the two models. Of the 42,257 patients included, 948 (2.24%) experienced VTE during hospitalization. According to the Padua score, 3,7513 (88.78%) of patients were considered low risk, while 4,744 (18.22%) were classified as high risk. The IMPROVE score identified 20,744 (49.09%) of patients as low risk, 20799(49.22%) as intermediate risk, and 714(1.69%) as high risk. The AUC for the Padua score was 0.735 (95% CI: 0.717-0.753), with a sensitivity of 49.4% and specificity of 89.6%. For the IMPROVE score, the AUC was 0.711 (95% CI: 0.693-0.729), with a sensitivity of 32.5% and specificity of 99.0%. The DeLong test, used to compare the AUCs, yielded a z-value of 1.886 with a P-value of 0.059, indicating no statistical difference. When assessing VTE risk in patients with stroke, cancer, nephrotic syndrome, and critical illness (ICU/CCU stay), both scoring models showed comparable predictive performance with AUCs ranging between 0.7 and 0.8. Both the Padua score and IMPROVE score have good predictive ability for VTE events during hospitalization in medical patients. Among them, the IMPROVE score has objective assessment items, simpler operation, and more detailed risk stratification, which is beneficial for clinicians to take physical and pharmacological preventive measures at different levels.ChiCTR2200056903, February 22, retrospectively registered.

Inaccuracy of Initial Clinical Mobility Assessment in Venous Thromboembolism Risk Stratification

BackgroundVenous thromboembolism risk increases in hospitals due to reduced patient mobility. However, initial mobility evaluations for thromboembolism risk are often subjective and lack standardization, potentially leading to inaccurate risk assessments and insufficient prevention. MethodsA retrospective study at a quaternary academic hospital analyzed patients using the Padua risk tool, which includes a mobility question, and the Johns Hopkins-Highest Level of Mobility (JH-HLM) scores to objectively measure mobility. Reduced mobility was defined as JH-HLM scores ≤3 over ≥3 consecutive days. The study evaluated the association between reduced mobility and hospital-acquired venous thromboembolism using multivariable logistic regression, comparing admitting health care professional assessments with JH-HLM scores. Symptomatic, hospital-acquired thromboembolisms were diagnosed radiographically by treating providers. ResultsOf 1715 patients, 33 (1.9%) developed venous thromboembolism. Reduced mobility, as determined by the JH-HLM scores, showed a significant association with thromboembolic events (adjusted OR: 2.53, 95%CI:1.23-5.22, P = .012). In contrast, the initial Padua assessment of expected reduced mobility at admission did not. The JH-HLM identified 19.1% of patients as having reduced mobility versus 6.5% by admitting health care professionals, suggesting 37 high-risk patients were misclassified as low risk and were not prescribed thrombosis prophylaxis; 4 patients developed thromboembolic events. JH-HLM detected reduced mobility in 36% of thromboembolic cases, compared to 9% by admitting health care professionals. ConclusionInitial mobility evaluations by admitting health care professionals during venous thromboembolism risk assessment may not reflect patient mobility over their hospital stay. This highlights the need for objective measures like JH-HLM in risk assessments to improve accuracy and potentially reduce thromboembolism incidents.

The Association of Anticoagulation Intensity with Outcomes in Hospitalized COVID-19 Patients.

Venous thromboembolism (VTE) risk is increased in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A key question was whether increased intensity of anticoagulation would help prevent VTE and improve patient outcomes, including transfer to the intensive care unit (ICU) and mortality. At the start of the coronavirus disease-19 (COVID-19) pandemic, our institution, Boston Medical Center, instituted a VTE risk stratification protocol based on patients' initial D-dimer levels, medical history, and presence of thrombosis to determine whether they should receive standard-dose prophylaxis, high-dose prophylaxis, or therapeutic anticoagulation. We performed a retrospective observational cohort study examining the association of degree of anticoagulation with outcomes in 915 hospitalized COVID-19 patients hospitalized initially on the general inpatient wards between March 1,, 2020, and June 1, 2020. Patients directly hospitalized in the ICU were excluded. Most, 813 patients (89%), in our cohort were on standard-dose prophylaxis; 32 patients (3.5%) received high-dose prophylaxis; 70 patients (7.7%), were treated with therapeutic anticoagulation. VTE occurred in 45 patients (4.9%), and the overall in-hospital mortality rate was 5.4% (49 deaths). On multivariable analysis of clinical outcomes in relation to type of anticoagulation, in the high-dose prophylaxis group, there was a trend towards increased in-hospital mortality (odds ratio 2.4 (0.8-7.5, 95% CI)) and increased ICU transfer (odds ratio 2.2 (0.9-5.7, 95% CI)). Our results suggest that patients receiving high-dose prophylaxis had more severe disease that was not mitigated by intermediate-dose anticoagulation.

A Predictive Model for Cancer-Associated Thrombosis in Japanese Cancer Patients: Findings from the J-Khorana Registry.

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.

Risk factors for venous thromboembolism in patients with pneumonia in the pre-COVID-19 era: a meta-analysis and systematic review.

Elevated risk of venous thromboembolism (VTE) in patients with coronavirus disease 2019 (COVID-19) pneumonia has been recognized, while the risk factors associated with VTE in patients with non-COVID-19 pneumonia remain to be defined. This study aimed to conduct a meta-analysis and systematic review following Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to identify potential risk factors for VTE in patients with pneumonia from the pre-COVID-19 era. PubMed, EMBASE, and Cochrane Library were searched. Two reviewers performed screening, full-text review, and extraction. Risk factors and odds ratio (OR) were estimated. Of 595 articles identified, six studies were included. Pooled analysis suggested that age ≥60 years [OR =2.75, 95% confidence interval (CI): 2.55-2.97, P<0.001], mechanical ventilation (MV) (OR =9.48, 95% CI: 8.24-10.91, P<0.001), hypertension (OR =1.41, 95% CI: 1.09-1.83, P=0.010), diabetes (OR =1.49, 95% CI: 1.36-1.64, P<0.001), heart failure (OR =3.15, 95% CI: 1.05-9.41, P=0.040) and cancer (OR =2.86, 95% CI: 2.07-3.95, P<0.001) were associated with higher risk for deep vein thrombosis in patients with pneumonia. While age ≥60 years (OR =2.46, 95% CI: 2.21-2.73, P<0.001), bacterial pneumonia (OR =3.80, 95% CI: 1.65-8.73, P=0.002), hyperlipidemia (OR =1.55, 95% CI: 1.00-2.41, P=0.049), heart failure (OR =2.70, 95% CI: 2.05-3.56, P<0.001), chronic obstructive pulmonary disease (OR =4.73, 95% CI: 3.11-7.17, P<0.001) and cancer (OR =2.90, 95% CI: 2.39-3.53, P<0.001) were risk factors for pulmonary embolism in patients with pneumonia. Patients with non-COVID-19 pneumonia, particularly those with advanced age, MV, cardiovascular comorbidities or cancer, warrant individualized management during hospitalization. Our findings could contribute to refining risk prediction models and further risk stratification for VTE in patients with pneumonia in clinical practice.

CDKN2C Deletion on 1p32 Locus As Part of Irwazh Score, a New Risk Assessment Model for Venous Thromboembolism Occurring within 6-12 Months of Treatment Initiation in Newly Diagnosed Multiple Myeloma

Background Adequate risk-stratification of venous thromboembolism (VTE) in multiple myeloma (MM) is an unmet need. Methods This is a retrospective study of 320 newly diagnosed MM (NDMM) patients treated from 2011 to 2023. All gave their informed consent. Required minimal follow-up (FU) length was 12 months or lower if VTE or death occurred. We aimed to evaluate VTE incidence at 6 and 12 months of first line treatment (L1) initiation, identify risk predictors and assess VTE impact on overall survival (OS). Comorbidities, baseline demographic (excluding race), clinical, biological (including FISH) and imaging data, treatment exposures, response profile and OS were all analyzed. Total scores for 4 existing risk assessment models (RAM) (IMPEDE-VTE, SAVED, PRISM, IFM/DFCI-related) were also calculated from L1 start. VTE events (VTEe) were adjudicated to exclude superficial ones and restrict analysis to documented deep vein thrombosis (DVT) and pulmonary embolism (PE). Predictors validated by Cox model were weighted based on their hazard ratios (HR). Results The cohort comprised 147 (45.9%) women and 111 (34.7%) transplant-eligible patients. Overall median age was 70.1 (36.6-98.4) years and 205 (64.1%) subjects were &amp;gt;65. Two hundred and twenty-five (70.3%) received standard-of-care regimens containing immunomodulatory drugs (IMID) (Thalidomide in 98: 30.6%; Revlimid in 127: 39.7%), while 130 (40.6%) received high-dose (≥160 mg) Dexamethasone (HDD) per L1 cycle. VTE prophylaxis was omitted in 32 (10%) or consisted of NSAID in 97 (30.3%), prophylactic low molecular weight heparin (LMWHp) in 115 (36%) and direct oral anticoagulant (DOA) in 55 (17.2%), while 10 (3.1%), 9 (2.8%) and 2 (0.6%) were previously receiving curative LMWH (LMWHc), vitamin K antagonist (VKA) or a mixed regimen, respectively, for prior VTE or other indications. In 33 (10.3%) patients, 34 VTEe occurred (31 [91.2%] within the first 6 months): 4 (11.8%) as both PE and DVT; 3 (8.8%) as PE; 27 (79.4%) as isolated proximal (12 [35.3%]) or distal (15 [44.1%]) DVT of the upper (2 [5.9%]) or lower (25 [73.5%]) limbs, including 3 (8.8%) with both proximal and distal and 3 (8.8%) close to central venous catheter. Based on Cox univariate analysis, VTEe were not related to usual parameters such as past VTE history, IMID, HDD or EPO exposure, prophylaxis omission or modality or recent surgery. A 6-parameter RAM, named Irwazh score, was built from multivariate Cox model, including: age &amp;lt;55 years (HR 0.34; 95% confidence interval [CI]: 0.0-0.8; p=0.014), prior diabetes (HR 3.41; 95% CI: 1.48-7.85; p=0.004), creatinine clearance (Cr-Cl) using MDRD &amp;lt;40 ml/mn (HR 2.64; 95% CI: 1.26-5.51; p=0.009), CRP ≥10 mg/dl (HR 2.65; 95% CI: 1.27-5.48; p=0.009), ≥50% 1p32 deletion (HR 3.44; 95% CI: 1.17-10.09; p=0.024) and minimal response (MR) to L1 (HR 4.67; 95% CI: 1.71-12.73; p=0.003). Area under the curve (AUC) was 0.718 (95% CI: 0.624-0.811; p&amp;lt;0.0001) at 12 months and 0.731 (95% CI: 0.636-0.825; p&amp;lt;0.0001) at 6. In comparison, AUC was 0.649 (95% CI: 0.546-0.751; p=0.004) for IMPEDE-VTE, 0.597 (95% CI: 0.505-0.689; p=0.039) for PRISM, 0.584 (95% CI: 0.486-0.682: p=0.091) for IFM/DFCI-related and 0.580 (95% CI: 0.473-0.687; p=0.141) for SAVED (Figure 1). Based on points attributed to each parameter (age &amp;lt;55 years: 1; prior diabetes: 9; Cr-Cl&amp;lt;40 ml/mn: 6; CRP≥10 mg/dl: 6; ≥50% 1p32 deletion: 9; MR: 11), patients were stratified into low (&amp;lt;6 points), intermediate (6-15) and high risk (≥16), with 12-month cumulative VTE incidence of 4,51% (6/133), 10,45% (16/153) and 35,29% (12/34), respectively. Of low-risk patients, 2 were receiving NSAID and 4 LMWHp; of intermediate-risk ones, 2 had no prophylaxis, 9 were under NSAID and 5 LMWHp; of high-risk ones, 2 had no prophylaxis, 5 were receiving NSAID, 2 LMWHp, 1 VKA, 1 LMWHc and 1 DOA. Using Kaplan-Meier analysis for VTE-free survival, statistical difference was found significant between low- and intermediate-risk ( p=0.043), low- and high-risk ( p&amp;lt;0.0001) and intermediate- and high-risk groups ( p=0.000) (Figure 2). Median total FU was 33.2 (0.2-147) months; OS assessment using Cox model did not find a significant statistical impact of VTE neither at 6 ( p=0.491) and 12 ( p=0.199) months nor during the whole FU length ( p=0.438). Conclusion The Irwazh score, with an unprecedented FISH feature, a statistically significant risk-stratifying power and a better AUC than existing VTE RAMs is worth validating in a larger clinical study.

Blood Biomarkers and Risk of Venous Thromboembolism in Cancer Patients: A Systematic Review and Meta-Analysis

Patients with cancer have an increased risk of venous thromboembolism (VTE). Currently, several VTE risk prediction tools have been developed to identify candidates for primary VTE thromboprophylaxis. However, the availability of reliable and highly discriminatory prediction models for VTE risk assessment in cancer patients is limited, warranting further improvement of VTE risk stratification strategies. The implementation of biomarkers in risk assessment models might lead to refined VTE risk prediction, but it remains to be more comprehensively investigated. In this systematic review and meta-analysis, we aimed to evaluate and summarize all candidate biomarkers and their association with cancer-associated VTE. We conducted an electronic search in Medline, EMBASE and Cochrane central databases for studies that evaluated biomarkers in adult patients with cancer from inception to September 26 th 2022. We included observational and interventional studies reporting on subsequent VTE occurring after a cancer diagnosis. The baseline or index event of the biomarker measurements had to be definitively and uniformly applied to all enrolled patients. Two reviewers independently screened titles, abstracts and full-text articles for inclusion. Median differences (for continuous measures) and Odds Ratios (OR) (for dichotomous cut-off measures) with 95% confidence intervals (95% CI) were estimated and pooled using random-effects models. We assessed each studies risk of bias using the Quality in Prognostic Studies (QUIPS) risk of bias tool. Our search identified 4274 studies that were screened for inclusion (Figure 1). Following the screening, 109 studies (with 520 biomarker measurements) met the inclusion criteria and were included in the systematic review. Of these, 51 studies (with 174 biomarker measurements) were included in the meta-analysis. The majority of the studies were cohort studies (n=47; 32 prospective and 15 retrospective), while the other 4 studies were nested case-control studies. Eighteen studies had a study population of mixed cancer types and the remaining studies had a study population of specific cancer types, including: lung (n=6), gynecologic (n=5), breast (n=3), stomach (n=3), lymphoma (n=2), myeloma (n=2), ovarian (n=2), pancreas (n=2), brain (n=1), colorectal (n=1), gastrointestinal (n=1), genitourinary (n=1), gynecologic or breast (n=1), head and neck (n=1), liver (n=1), and prostate (n=1). We calculated the median difference and 95% CI for 23 different biomarkers. Cancer patients who experienced subsequent VTE events had significantly higher pre-treatment factor VIII activity, peak thrombin, platelet count and prothrombin fragment F1+2 levels compared to patients who did not experience VTE events (Table 1). Pre-treatment d-dimer levels were also higher in cancer patients who developed VTE, however, considerable heterogeneity was observed (Table 1). Contrastingly, pre-treatment hemoglobin, lag time - thrombin generation, prothrombin time and time to peak thrombin levels were significantly lower in those experiencing VTE events compared to patients who did not experience any events (Table 1). D-dimer levels on day-1 after cancer surgery were reported in two studies which, when pooled, revealed that cancer patients with subsequent VTE had higher d-dimer levels post-operatively compared to those with no events (Table 1). Moreover, pre-treatment hemoglobin levels 100 g/L was significantly associated with future VTE risk [OR: 1.42 (95%CI: 1.03-1.97), I 2=0%, n=11] while neutrophil lymphocyte ratio 3 was associated, yet insignificant [OR: 1.60 (95%CI: 0.99-2.60), I 2=43%, n=4]. Pre-treatment platelet count 350 x 10 9/L and white blood count levels 11 x 10 9/L were not significantly associated with future VTE risk [OR: 0.84 (95%CI: 0.66-1.06), I 2=0%, n=9 and 1.32 (0.86-2.03), I 2=56%, n=8, respectively]. From the 51 studies included in the meta-analyses, 27 studies had a low risk of bias, 19 studies had a moderate risk of bias and 5 studies had a high risk of bias. In conclusion, nine blood biomarkers were found to be significantly associated with VTE in cancer patients. Their utility as predictors of VTE in thrombotic risk assessment models may help in optimising VTE prediction and should be further explored in future studies.

Inaccuracy of Initial Clinical Mobility Assessment in Venous Thromboembolism Risk Stratification

Background: The risk of Venous Thromboembolism (VTE) often escalates in hospital settings in part due to reduced patient mobility. However, mobility assessment for VTE risk determination is often clouded by lack of clear definitions and standards. This vagueness can result in erroneous evaluations, especially near the time of admission, particularly since a patient's mobility is not static but fluctuates throughout the hospital stay. Methods: We conducted a retrospective cohort analysis of patients who were discharged from medicine services in a large academic hospital. For each of these patients, daily nurse-collected Johns Hopkins-Highest Level of Mobility (JH-HLM) scores were used to calculate an objective measure of mobility. Reduced mobility was defined as an JH-HLM score of ≤3 on three consecutive days during hospitalization. We compared this definition of reduced mobility with clinician reported immobility as reflected by Padua scores entered on admission as part of mandatory VTE risk stratification. We also assessed the association between immobility and VTE using an adjusted odds ratio controlling for other VTE risk factors. Results: Out of 1715 included patients, clinicians identified only 111 (6.5%) as having reduced mobility compared with 328 patients (19.1%) using the JH-HLM calculated approach. If the JH-HLM calculated measure of reduced mobility had been utilized, it would have led to the reclassification of 37 patients from a low-risk category to a high-risk category for VTE. In the cohort, 33 of 1715 (1.9%) patients developed VTE. Among these patients, JH-HLM calculated reduced mobility was identified in 12/33 (36%) of patients, whereas clinicians identified reduced mobility in 3/33 (9%) of patients. Presence of JH-HLM calculated reduced mobility was significantly associated with VTE events (aOR: 2.53, 95% CI: 1.23 - 5.22, P = 0.012). Clinician assessed reduced mobility at the time of admission was not associated with VTE events. Conclusion: The initial clinician's assessment of mobility during VTE risk assessment did not accurately capture the extent of reduced mobility during the patient's hospitalization. These findings highlight the importance of employing objective measures of patient mobility for assessing and reassessing VTE risk throughout the hospital stay. Healthcare organizations should consider implementing objective measures of mobility like the JH-HLM to improve VTE risk assessment and potentially reduce the occurrence of VTE.

Development and External Validation of a Lymphoma-Specific Venous Thromboembolism Risk Assessment Model

Introduction: Venous thromboembolism (VTE) significantly affects cancer patients undergoing systemic therapy. Existing risk models developed in the pan-cancer population, such as the Khorana score, offer limited discrimination in cancer-specific setting. We aimed to develop and validate a risk assessment model (RAM) tailored for lymphoma patients, accounting for the clinical and sociodemographic heterogeneity across three distinct healthcare systems in the United States. Methods: Electronic health records (EHR) linked to cancer registry 2006-2021 from the Veterans Affairs national healthcare system (VA) with a total of 10,313 lymphoma patients were randomly divided into an 80% derivation cohort and a 20% internal validation cohort. Further external validation was carried out using data from two other healthcare systems - Harris Health System (HHS, N= 854, 2011-2020) and MD Anderson Cancer Center (MDACC, N=1,858, 2017-2020). Patients were included if they had newly diagnosed lymphoma requiring first-line systemic therapy within 1 year of diagnosis. Patients were excluded if they had recent diagnosis of acute VTE within the last 6 months or were prescribed anticoagulant within 1 month before index date. The index date was the time of systemic therapy, and all covariates were extracted on or before the index date. Incident VTE was defined using our published computable phenotype algorithm (PMID 36626707; 37067102). For RAM derivation (Figure 1), 32 candidate predictors were initially chosen based on clinical relevance and EHR data availability. Missing values were imputed via chain random forest. Parsimonious variable categories were selected by a combination of Least Absolute Shrinkage and Selection Operator (LASSO), Recursive Feature Elimination (RFE), and random forest to generate the final logistic regression model. For external validation, complete case analysis was performed using the derived beta coefficients without model refitting. Bootstrapped time-dependent c statistics and calibration curves for 6-month VTE were used to assess discrimination and fit. A pre-determined threshold of 8% VTE at 6-month from the predicted probability was used to stratify high vs. low-risk groups. Competing risk models were used to assess cumulative incidence. Results: At 6 months, the VTE incidence were 5.75% (n=469) in VA derivation and 6.12% (n=124), 8.24% (n=69), and 6.55% (n=112) in the VA, HHS, and MDACC validation cohorts, respectively. The three healthcare systems had different baseline characteristics in demographics, lymphoma types, systemic therapies, and comorbidities. Patients from VA were mostly older males with more comorbidities and remote history of VTE, patients from HHS were mostly uninsured minorities who were younger but with more aggressive histology, while those from MDACC were patients treated at a comprehensive cancer center. The variables in the final RAM included lymphoma type (4 groups ranging from very-low to very-high risk), body mass index, indwelling catheter, cytotoxic vs. targeted therapy, history of VTE, recent hospitalization, and paralysis/immobilization. Table 1 shows the variable prevalence in each cohort. As shown in Figure 1, the new RAM showed promising discrimination for VTE with a C-statistic of 0.69 in the derivation cohort and 0.67, 0.70, 0.72 in the internal and two external validation cohorts. By splitting patients using an 8% predicted risk threshold, the high- vs. low-risk group achieved a clear differentiation in risk stratification despite significant differences in baseline characteristics. This represented a noticeable improvement for lymphoma patients over the Khorana Score, which yielded C-statistics of 0.53-0.56. The overall calibration of the RAM appeared adequate. Conclusions: Using multiple cancer-EHR cohorts with heterogeneous patients and a wide range of lymphoma subtypes, we successfully derived and externally validated an improved RAM for VTE specifically in lymphoma patients requiring early initiation of systemic therapy. Along several well-known patient-specific risk factors, lymphoma type was an important predictor of VTE risk. The new RAM could improve VTE risk stratification and prevention efforts in lymphoma patients.

DNA Liquid Biopsies for Cancer-Associated Venous Thromboembolism Prediction

Introduction Cancer-associated venous thromboembolism (VTE) is a major source of oncologic cost, morbidity and mortality. Identifying an optimal population for prophylactic anticoagulation is challenging and adds to clinician overhead. Circulating tumor (ct)DNA sequencing assays (“liquid biopsies”) are increasingly deployed in clinic, with multiple US FDA approvals for matching to molecularly targeted therapy. Preliminary data suggest that cell-free (cf)DNA, which is also measured as part of liquid biopsies and may consist of tumor or wild-type DNA, is thrombogenic due to its association with neutrophil extracellular traps. However, clinical validation of cfDNA for VTE prediction is lacking. ctDNA detection is associated with aggressive tumor biology and worse survival; however, whether it is associated with VTE is unknown. To address these gaps, we studied the clinical utility of ctDNA and cfDNA from liquid biopsies for predicting VTE. Methods We conducted an observational study in two cohorts: 1) Patients with any cancer type at Memorial Sloan Kettering Cancer Center (MSK, New York USA), an academic medical center, with plasma ctDNA sequencing using MSK-ACCESS, a NY State-approved, 129-gene assay (N=4,141). 2) A nonoverlapping cohort of patients at MSK or GenesisCare (Sydney, Australia), a community oncology setting, with stage IV or recurrent non-small cell lung cancer and ctDNA sequencing using a separate commercial assay (Agilent ctDx Lung, N=463). We studied the independent contribution of ctDNA, cfDNA and related variables for predicting VTE using Cox proportional hazards. We studied the potential utility of DNA liquid biopsies for predicting VTE within six months using machine learning models, comparing their dynamic area under the receiver operating curve, precision, and recall to those of the Khorana score, the most widely implemented risk metric. We tested the impact of ongoing anticoagulation for non-VTE indications on future VTE in patients with and without detectable ctDNA using nonrandomized, real-world evidence. Results ctDNA detection was associated with an increased risk of VTE in a dose-dependent manner (Figure 1). This association was observed across assays and treatment sites and regardless of genomic subtype. ctDNA was associated with VTE risk in non-small cell lung, breast, pancreatic, prostate, and less represented cancers as well as melanoma but not in bladder, hepatobiliary, or colorectal cancer. By contrast, cfDNA concentration was associated with VTE risk in all cancer types. In multivariate analysis, ctDNA detection, cfDNA concentration, Khorana score, chemotherapy treatment within 30 days, and number of organ sites of metastasis were all independently associated with VTE. In a cohort of patients with treatment naive lung adenocarcinoma with segmented positron emission tomography scans, ctDNA was an independent predictor of VTE after controlling for metabolic tumor volume. A random survival forest machine learning model to predict VTE within six months of plasma draw using liquid biopsy data (i.e. cfDNA and ctDNA levels as well as genomic content), cancer type, and chemotherapy receipt (“LB+”) outperformed the Khorana score in 5-fold cross-validation and was similarly superior in the external lung cohort (Table 1). The superiority of the model was observed in patients treated or not treated with chemotherapy. Additional clinical and radiologic data, including demographics, metastatic sites of disease, and Khorana score components (“All”), did not improve the ctDNA assay-based LB+ model. Patients with anticoagulation had lower VTE rates if ctDNA was detectable (adjusted HR 0.54, 95%CI 0.33-0.87) but not if ctDNA was undetectable. Conclusion In patients with cancer, ctDNA and cfDNA are independent biomarkers for VTE. Risk models incorporating liquid biopsy data are feasible in academic or community settings and, if prospectively validated, would provide a means of VTE risk stratification at scale.

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.

Impact of integrating standardized venous thromboembolism (VTE) prophylaxis orders for patients with multiple myeloma into an electronic health record (EHR).

469 Background: VTE is a serious complication in multiple myeloma patients, who have a 9-fold increased risk compared to the general population. Prophylaxis for VTE is recommended by international guidelines in multiple myeloma patients based on VTE risk assessment, but published studies have demonstrated prescribing may be suboptimal. Our aim was to evaluate the impact of integrating standardized VTE prophylaxis orders for multiple myeloma patients on active treatment into our EHR, which services over 2300 providers within 500 community cancer treatment locations across the United States. Methods: National Comprehensive Cancer Network Guideline-recommended VTE prophylaxis agents were integrated as optional orders into multiple myeloma EHR regimen templates from June to July 2022. Optional informational orders were also included: a “VTE Prophylaxis Reminder” order served as a trigger for the care team if prophylaxis was not prescribed and a “VTE Prophylaxis Exception” order served as documentation if the patient did not qualify for anticoagulation. An educational guide about VTE risk stratification and prophylaxis in multiple myeloma was developed and embedded in regimen templates. To evaluate the impact of this intervention, a structured EHR data export was used to identify multiple myeloma patients with regimen templates ordered during the prespecified time frames. A retrospective chart review was conducted to identify documentation of anticoagulation or reason for exception on or prior to cycle 1 day 1 of the multiple myeloma regimen. Data were compared using the Fisher’s exact test. We also evaluated ordering of VTE prophylaxis and use of informational orders from regimens during the post-implementation phase. Results: A total of 297 patients were identified, with 128 during the pre-implementation phase (May 2022) and 169 during the post-implementation phase (September 2022). Documentation of anticoagulation or reason for exception on or prior to cycle 1 day 1 of the multiple myeloma regimen increased from 70% (89/128) during the pre-implementation phase to 81% (137/169) during the post-implementation phase (two-sided p=0.0276). Aspirin was the most common agent prescribed in 73% and 64% of patients, respectively. During the post-implementation phase, VTE prophylaxis was prescribed directly from the regimen in 16% of patients. The “VTE Prophylaxis Reminder” order was utilized for 89% of patients and the “VTE Prophylaxis Exception” order was utilized for 1 patient. Conclusions: Integration of standardized orders into EHR regimen templates may facilitate prescribing and serve as reminders for the care team. We saw an 11% increase in documentation of VTE prophylaxis, which may potentially reduce risk of VTE in this patient population. Efforts are ongoing to highlight the need for anticoagulation and importance of documentation.