Risk Of Venous Thromboembolism In Cancer Patients Research Articles

The pathogenesis of cancer-associated thrombosis.

Patients with cancer have a higher risk of venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary embolism (PE), compared to the general population. Cancer-associated thrombosis (CAT) is a thrombotic event that occurs as a complication of cancer or cancer therapy. Major factors determining VTE risk in cancer patients include not only treatment history and patient characteristics, but also cancer type and site. Cancer types can be broadly divided into three groups based on VTE risk: high risk (pancreatic, ovarian, brain, stomach, gynecologic, and hematologic), intermediate risk (colon and lung), and low risk (breast and prostate). This implies that the mechanism of VTE differs between cancer types and that specific VTE pathways may exist for different cancer types. This review summarizes the specific pathways that contribute to VTE in cancer patients, with a particular focus on leukocytosis, neutrophil extracellular traps (NETs), tissue factor (TF), thrombocytosis, podoplanin (PDPN), plasminogen activator inhibitor-1 (PAI-1), the intrinsic coagulation pathway, and von Willebrand factor (VWF).

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.

Machine-Learning-Assisted Procoagulant Extracellular Vesicle Barcode Assay toward High-Performance Evaluation of Thrombosis-Induced Death Risk in Cancer Patients.

Venous thromboembolism (VTE) is the most fatal complication in cancer patients. Unfortunately, the frequent misdiagnosis of VTE owing to the lack of accurate and efficient evaluation approaches may cause belated medical intervention and even sudden death. Herein, we present a rapid, easily operable, highly specific, and highly sensitive procoagulant extracellular vesicle barcode (PEVB) assay composed of TiO2 nanoflower (TiNFs) for visually evaluating VTE risk in cancer patients. TiNFs demonstrate rapid label-free EV capture capability by the synergetic effect of TiO2-phospholipids molecular interactions and topological interactions between TiNFs and EVs. From ordinary plasma samples, the PEVB assay can evaluate potential VTE risk by integrating TiNFs-based EV capture and in situ EV procoagulant ability test with machine-learning-assisted clinical data analysis. We demonstrate the feasibility of this PEVB assay in VTE risk evaluation by screening 167 cancer patients, as well as the high specificity (97.1%) and high sensitivity (96.8%), fully exceeding the nonspecific and posterior traditional VTE test. Together, we proposed a TiNFs platform allowing for highly accurate and timely diagnosis of VTE in cancer patients.

Incidence of venous thromboembolism with immune checkpoint inhibitors in a community setting: A single-center retrospective study.

e14681 Background: Immune activation and inflammation caused by immune checkpoint inhibitors (ICIs) are critical pathobiological drivers for venous thromboembolism (VTE). There is a paucity of data about VTE risk in cancer patients receiving ICI. We aimed to describe the incidence of VTE in cancer patients receiving ICI in a community setting. Methods: We conducted a single center, retrospective cohort study at Saint Vincent Hospital. The study cohort was created using our center's pharmacy database of patients who received any of the five ICIs (ipilimumab, nivolumab, pembrolizumab, atezolizumab, or durvalumab) between Jan 2017 and Dec 2022. VTE events including deep venous thrombosis, splanchnic vein thrombosis, and pulmonary embolism, were identified by chart review. We used a self-controlled risk-interval design, with "control period" and "at-risk period" being 6 months before and after the initiation of ICI treatment respectively. VTE events were also analyzed for subgroups: Single-agent ICI therapy (IA), Dual ICI therapy (IB), and ICI + chemotherapy (IC). Descriptive statistics and cox regression were used for statistical analysis. Results: Study population included 170 patients, with 75, 14, and 81 patients in subgroups IA, IB, and IC respectively. The mean age of the patients was 69.51 ± 10.05 years with a majority being males (62.4%). The most common cancer observed was non-small cell lung cancer (43.5%) followed by small cell lung cancer (6.9%), and malignant melanoma (5.7%). Pembrolizumab (55.3%) was the most common ICI used and nivolumab + ipilimumab (7.64%) was the most common dual ICI used. We noted a 1.25-fold higher incidence of VTE post-ICI use (Incidence rate ratio [IRR]: 11.76 per 100 person-year) compared to pre-ICI use (IRR: 9.41 per 100 person-year) at 6 months. On subgroup analysis, Group IB had the highest risk for VTE at 6 months (IRR: 28.57 per 100 person-year), followed by group IC and IA (IRR: 14.12 and 8.0 per 100 person-year respectively). IRR decreased to 6.62 per 100 person-year at 12-month interval indicating increased VTE risk in the first 6 months of ICI exposure. Type of ICI, adjuvant chemotherapy or type of cancer was not able to predict VTE risk on multivariate analysis. Conclusions: ICI treatment was associated with an increased incidence of VTE in our study cohort with the highest risk among patients on dual ICI followed by ICI + chemotherapy and ICI monotherapy. Future prospective studies are needed to identify risk factors and biomarkers to improve risk stratification and risk-adapted thromboprophylaxis.[Table: see text]

The potential of folic acid and homocysteine as novel serum markers for venous thromboembolism in cancer patients.

Venous thromboembolism (VTE) is a common coagulative dysfunctional complication of cancer patients. The present study aimed to determine the association and diagnostic values of serum homocysteine (Hcy) and folic acid levels with VTE in cancer patients. We enrolled 700 cancer patients and 100 healthy subjects in our study. All cancer patients, with or without VTE, underwent measurement of serum Hcy and folic acid levels and coagulative markers including D-Dimer, factor VIII, fibrinogen and tissue plasminogen activator. The diagnostic values of Hcy and folic acid were assessed by receiver operative characteristic (ROC) analysis. Correlations between Hcy and folic acid and coagulative factors were determined. Among the 700 patients with malignant tumors recruited in our study, a total of 89 patients had VTE combined within three months, and 611 patients did not have VTE. Cancer patients with VTE had significantly higher levels of Hcy and significantly lower levels of folic acid in serum. Both Hcy and folic acid in serum demonstrated high sensitivity and specificity in diagnosing VTE in cancer patients and showed strong correlations to coagulative markers. Hcy and folic acid, which have strong correlations to coagulative markers, are potential novel serum markers for stratifying VTE risk in cancer patients.

Thrombin Generation As a Predictive Biomarker for Venous Thromboembolism in Patients with Pancreatic and Lung Cancer Undergoing Systemic Therapy

Introduction:Venous thromboembolism (VTE) is common in patients with active malignancy. Whilethromboprophylaxis can mitigate this risk, current guidelines do not support routine use as the benefit ismodest and maybe negated by an increase in bleeding complications. However, there is significantvariation in VTE risk within the cancer population, thus prophylaxis can be considered in high-riskpatients. The Khorana score (KS) is validated to predict chemotherapy-associated VTE; however, it hasseveral limitations including variable performance based on tumor type as well as a static riskcategorization, based on pre-chemotherapy laboratory data, rather than a continuous assessment.Thrombin generation (TG) is an emerging biomarker that assesses global coagulation activation andpredicted increased VTE risk in cancer patients in the Vienna Cancer and Thrombosis Study (PMID:21464402). This study enrolled a heterogeneous cancer population, however, peak TG was not reportedby tumor type nor were the TG levels monitored over time in response to systemic therapy. The primaryaim of this study was to assess the relationship between TG (both peak TG and endogenous thrombinpotential, ETP) and KS. Secondary outcomes were to evaluate the impact of systemic therapy on peakTG and ETP levels over time and to assess the relationship between TG and clinical outcomes.Methods:This was a prospective study that enrolled adults with newly diagnosed, locally advanced or metastaticadenocarcinoma of the lung or pancreas. All patients received their care at Dartmouth HitchcockMedical Center. Those with a history of active VTE or use of full dose anticoagulant within 30 days priorto enrollment were excluded. After informed consent, KS was calculated and blood was collected insodium citrate tubes at 3 different time points (at initiation of therapy, and at the beginning of the 2 ndand 3 rd cycles of systemic therapy). Platelet-poor plasma was prepared by centrifugation and stored at -80°C until analysis by calibrated automated thrombogram (CAT; Thrombinoscope BV, Maastricht,Netherlands) using 1 pM tissue factor and 4 uM phospholipids to trigger coagulation reactions.Measurements were performed in triplicate for each specimen, and raw data were converted to peakTG and ETP. Information about VTE events, response to treatment and survival was obtained by chartreview. Mean and standard deviation were calculated for continuous variables and unpaired T test wasused for statistical analysis.Results:We report the results from 32 participants (17 lung, 15 pancreas). The majority of patients hadmetastatic disease (94%) and all received systemic therapy. The median age was 67 and 56% ofparticipants were male. The KS breakdown for the cohort was: KS1, 25%; KS2, 53%; KS3, 19%; KS4, 3%.Mean peak TG was 279, 352, 487 and 325 nmole and mean ETP was 1320, 1653, 2252, 1726 nmole/minfor KS 1, 2, 3 and 4, respectively. Initial peak TG and ETP levels were significantly higher in the KS ≥2group compared to those with KS=1 (peak TG: 384 ±135 vs 279 ±82, p 0.047; Initial ETP: 1806 ±632 vs1320 ±286, p 0.045). There were 8 VTE events (25%) with all but one occurring in the pancreatic cancercohort; all events occurred in KS 2 and 3 groups (75% and 25% respectively). No statistically significant difference was observed for initial peak TG or ETP in those with VTE vs those without (Peak TG: 342±171 vs 363 ±119, p 0.701; ETP: 1736 ±720 vs 1667 ±571, p 0.783). Both peak TG and ETP decreased inresponse to systemic therapy (initial peak TG vs final: 376 ±115 vs 225 ±125, p 0.0001; initial ETP vs final:1799 ±498 vs 1254 ±423, p 0.0003). No significant difference in survival was noted based on initial ETPlevel of <1500 nmole/min vs ≥1500 nmole/min (574 ±620 vs 287 ±227, p 0.069).Conclusions:There appears to be an association between KS and peak TG and ETP. In addition, both peak TG and ETPdeclined in response to systemic therapy, suggesting that the degree of coagulation activation is relatedto tumor burden. Our findings in this small study support further investigation of TG for VTE riskassessment in cancer patients. Future strategies incorporating TG into risk stratification models mayallow oncologists to better identify the population that may benefit most from pharmacologicthromboprophylaxis.Funding: Northern New England Clinical Oncology DisclosuresNo relevant conflicts of interest to declare.

Thrombin Generation As a Predictive Biomarker for Venous Thromboembolism in Patients with Pancreatic and Lung Cancer Undergoing Systemic Therapy

Introduction: Venous thromboembolism (VTE) is a leading cause of death in cancer patients, but routine thromboprophylaxis is untenable due to an unacceptably high rate of bleeding complications and judicious patient selection is critical. The Khorana score (KS) predicts the risk for chemotherapy-associated VTE, but the score has limitations because it is assessed only at one time point prior to initiation of treatment. Thrombin generation (TG) is a novel biomarker that assesses global coagulation activation and predicted increased VTE risk in cancer patients in the Vienna Cancer and Thrombosis Study (CATS). In CATS, patients with high peak TG had a 3- fold increased risk for VTE compared to those with low peak TG. A limitation of the study was that it enrolled a heterozygous cancer patient population, and peak TG was not reported by tumor type. Additionally, TG was only measured at enrollment into the study, not over time. The primary aim of our study was to determine if assessment of TG (both peak TG and endogenous thrombin potential (ETP)) improves VTE risk prediction compared to the KS alone during systemic therapy for lung and pancreas cancer. A secondary objective was to evaluate the impact of systemic therapy on peak TG and ETP over time.Methods: This is an ongoing prospective study enrolling adults with newly diagnosed locally advanced or metastatic adenocarcinoma of the lung or pancreas who will receive their cancer therapy at Dartmouth Hitchcock Medical Center. Those with a history of active VTE or use of full dose anticoagulant medication within 30 days prior to enrollment are excluded. After informed consent, KS is calculated and blood is collected in sodium citrate tubes at 3 different time points (at initiation of therapy, and at the beginning of the 2nd and 3rd cycles of systemic therapy). Platelet-poor plasma is prepared by centrifugation and stored at -80°C until analysis by calibrated automated thrombogram (CAT; Thrombinoscope BV, Maastricht, Netherlands) using 1 pM tissue factor and 4 uM phospholipids to trigger coagulation reactions. Measurements are performed in triplicate for each specimen, and raw data are converted to peak TG and ETP. Information about symptomatic VTE events within 6 months of study entry is collected from the medical record.Results: We present the results for 15 patients who have completed study-related procedures to date, including 6 lung and 9 pancreatic cancer patients with a median age 61 and 69 years, respectively. The majority of patients had metastatic disease and all patients received systemic therapy. The KS breakdown for the cohort is: KS1, 7%; KS2, 60%; KS3 27%; KS4 7%. Mean peak TG were 341, 324, 641 and 890 nmole, and mean ETP were 1459, 1685, 2155, 2051 nmole/min for KS 1,2,3 and 4, respectively, and both peak TG and ETP decreased over time after cancer therapy. VTE occurred in 4 patients (27%), and the median KS was 2 for patients with and without VTE. Mean peak TG prior to initiation of chemotherapy was similar in patients with and without VTE (359 and 389 nmole, respectively) but mean ETP was higher in patients with VTE (1959 vs 1760 nmole/min, respectively).Conclusions: Though our sample size to date is small, preliminary results suggest that there is a direct correlation between KS and peak TG and ETP, and that ETP at diagnosis may be a more reliable predictor VTE than KS in lung and pancreatic cancer patients. Peak TG and ETP decreased progressively after initiation of systemic therapy, suggesting that the degree of coagulation activation is proportional to tumor burden. Though preliminary, these data suggest that TG is a promising biomarker of VTE risk. Enrollment to the study is continuing.Funding: This study was funded by Northern New England Clinical Oncology Society. DisclosuresNo relevant conflicts of interest to declare.

Risk factors for cancer‐associated venous thromboembolism: The venous thromboembolism prevention in the ambulatory cancer clinic (VTE‐PACC) study

BackgroundThe Khorana Score is a validated risk score for predicting 6‐month incidence of cancer‐associated venous thromboembolism (CAT) among patients starting chemotherapy. Venous thromboembolism (VTE) risk factors important in the general population, including age, sex, prior VTE, and hospitalization, are not included in this score, their association with VTE in cancer patients is unknown. ObjectiveTo examine risk factors for CAT and the impact of incorporating longitudinal hospitalization into risk assessment. MethodsRisk factors were recorded among patients starting chemotherapy at a single institution from 2012‐14. Hospitalization and time‐periods after hospitalization were assessed as time‐varying covariates. Logistic regression was used to determine factors related to 6‐month CAT risk (the Khorana Score endpoint). Proportional hazard models were used for risk factor identification throughout the 3‐year observation period. ResultsAmong 1,583 patients starting chemotherapy (mean age 60, 48% male), 187 developed CAT (11.8%) with 129 (69%) cases occurring within 6 months of starting chemotherapy. In the 6‐month analysis, no additional risk factors were associated with CAT. In the 3‐year analysis, male sex (HR 1.57, 95%CI 1.21, 2.07), prior VTE (HR 2.12, 95%CI 1.41, 3.18), and hospitalization (HR 2.69, 95%CI 1.92, 3.75) were associated with increased hazard of CAT, adjusting for risk factors in the Khorana score. ConclusionsWhen time‐to‐event data were incorporated into CAT risk assessment, male sex, prior VTE, and hospitalization were important risk factors. These data highlight the need to consider dynamic methods for assessing VTE risk in cancer patients, with particular attention to the period around hospitalizations.

Cancer-Associated Venous Thromboembolism.

Cancer patients are at high risk for venous thromboembolism (VTE) which is considered the second leading cause of death among this population. Both cancer and cancer treatment increase this risk. Since the risk of VTE is not the same in all cancer patients, it is important to understand what factors increase the risk of incident and the risk of recurrent VTE in this patient population. In an effort to combine multiple factors into a single risk stratification system, a scoring system for recurrent VTE risk in cancer patients has been developed and externally validated. While vitamin K antagonists (VKA) or the direct oral anticoagulants (DOACs) are first-line therapies for non-cancer-associated VTE treatment, low-molecular-weight heparin (LMWH) agents are the first-line anticoagulant for treatment of cancer-associated VTE. In this review, we discuss the epidemiology, pathophysiology, and risk stratification used in cancer-associated VTE. We also discuss the current therapies for cancer-associated VTE and the evidence supporting their use from the literature.

A shortened activated partial thromboplastin time predicts the risk of catheter-associated venous thrombosis in cancer patients

IntroductionHypercoagulability due to high coagulation factor levels resulting from host inflammatory response to cancer contributes to an increased risk of venous thromboembolism (VTE) in cancer patients. Central venous catheters (CVCs) further heighten this risk. Activated partial thromboplastin time (aPTT) can be used to broadly screen for elevated levels of relevant coagulation factors. Our objective was to determine if a shortened aPTT ratio (coagulation time of test- to- reference plasma) was a predictor of CVC-associated VTE in cancer patients. Materials and MethodsWe performed a retrospective case–control study on cancer patients undergoing tunneled CVC insertion at our center from 1999 to 2006 and identified 40 patients who had CVC-associated VTE. VTE was confirmed with color duplex ultrasonography or computed tomography scan. For each case, we obtained 5 controls that had the same cancer diagnosis and were matched on the following factors: age, chemotherapy, hormone therapy (if applicable), tobacco use, TNM staging and year of diagnosis. All patients had aPTT testing within 30days prior to surgery. We compared aPTT and aPTT ratio between cases and controls using Wilcoxon two sample test. ResultsaPTT ratio was significantly shorter in patients with CVC-related VTE as compared to controls [0.86 (95% confidence interval (CI) 0.78, 0.94) vs. 0.98 (0.94, 1.01), p=0.0003]. Mean aPTT was also significantly shorter. [25.6seconds (95% CI 23.2, 27.9) vs. 28.1 (26.9, 29.3), p=0.001] aPTT ratios of the controls tended to spread across larger aPTT ratio values whereas those of cases tended to clustered around the mean. ConclusionsCancer patients undergoing catheter placement who develop CVC-associated VTE have a shorter aPTT and aPTT ratio than those who do not develop VTE. aPTT, a simple and inexpensive test might be useful as a predictor of CVC-associated VTE risk in cancer patients.

Swimming and central venous catheter-related infections in the child with cancer

Hypercoagulability due to high coagulation factor levels resulting from host inflammatory response to cancer contributes to an increased risk of venous thromboembolism (VTE) in cancer patients. Central venous catheters (CVCs) further heighten this risk. Activated partial thromboplastin time (aPTT) can be used to broadly screen for elevated levels of relevant coagulation factors. Our objective was to determine if a shortened aPTT ratio (coagulation time of test- to- reference plasma) was a predictor of CVC-associated VTE in cancer patients.We performed a retrospective case–control study on cancer patients undergoing tunneled CVC insertion at our center from 1999 to 2006 and identified 40 patients who had CVC-associated VTE. VTE was confirmed with color duplex ultrasonography or computed tomography scan. For each case, we obtained 5 controls that had the same cancer diagnosis and were matched on the following factors: age, chemotherapy, hormone therapy (if applicable), tobacco use, TNM staging and year of diagnosis. All patients had aPTT testing within 30 days prior to surgery. We compared aPTT and aPTT ratio between cases and controls using Wilcoxon two sample test.aPTT ratio was significantly shorter in patients with CVC-related VTE as compared to controls [0.86 (95% confidence interval (CI) 0.78, 0.94) vs. 0.98 (0.94, 1.01), p = 0.0003]. Mean aPTT was also significantly shorter. [25.6 seconds (95% CI 23.2, 27.9) vs. 28.1 (26.9, 29.3), p = 0.001] aPTT ratios of the controls tended to spread across larger aPTT ratio values whereas those of cases tended to clustered around the mean.Cancer patients undergoing catheter placement who develop CVC-associated VTE have a shorter aPTT and aPTT ratio than those who do not develop VTE. aPTT, a simple and inexpensive test might be useful as a predictor of CVC-associated VTE risk in cancer patients.