Impact of Tumor Genomic Mutations on Thrombotic Risk in Cancer Patients.
ABSTRACT: Venous thromboembolism (VTE) is common in patients with cancer and is an important contributor to morbidity and mortality in these patients. Early thromboprophylaxis initiated only in those cancer patients at highest risk for VTE would be optimal. Risk stratification scores incorporating tumor location, laboratory values and patient characteristics have attempted to identify those patients most likely to benefit from thromboprophylaxis but even well-validated scores are not able to reliably distinguish the highest-risk patients. Recognizing that tumor genetics affect the biology and behavior of malignancies, recent studies have explored the impact of specific molecular aberrations on the rate of VTE in cancer patients. The presence of certain molecular aberrations in a variety of different cancers, including lung, colon, brain and hematologic tumors, have been associated with an increased risk of VTE and arterial thrombotic events. This review examines the findings of these studies and discusses the implications of these findings on decisions relating to thromboprophylaxis use in the clinical setting. Ultimately, the integration of tumor molecular genomic information into clinical VTE risk stratification scores in cancer patients may prove to be a major advancement in the prevention of cancer-associated thrombosis.
Project description:Venous thromboembolism (VTE) is a frequent cause of morbidity and mortality in cancer patients. A significant proportion of cancer-associated VTE occurs in the ambulatory setting and is associated with poorer outcomes and reduced survival. Risk for VTE is influenced by patient, cancer and treatment-specific factors.Recent studies have identified biomarkers associated with increased VTE risk in malignancy, including leukocyte and platelet counts, tissue factor, prothrombin split products, D-dimer, P-selectin, factor VIII and C-reactive protein. Recent and ongoing clinical trials have focused on VTE prophylaxis with low-molecular weight heparins in high-risk cancer outpatients, particularly those with pancreatic cancer. These studies have yielded encouraging preliminary results but whether thromboprophylaxis provides significant benefit to unselected cancer outpatients remains unclear.A risk stratification model incorporating known risk factors and biomarkers can identify those patients at highest risk. This review focuses on emerging data regarding risk assessment and benefit of thromboprophylaxis in patients with cancer.
Project description:Venous thromboembolism (VTE), comprising deep-vein thrombosis and pulmonary embolism, is a frequent complication in ambulatory cancer patients. Despite the high risk, routine thromboprophylaxis is not recommended because of the high number needed to treat and the risk of bleeding. Two recent trials demonstrated that the number needed to treat can be reduced by selecting cancer patients at high risk for VTE with prediction scores, leading the latest guidelines to suggest such an approach in clinical practice. Yet, the interpretation of these trial results and the translation of the guideline recommendations to clinical practice may be less straightforward. In this clinically-oriented review, some of the controversies are addressed by focusing on the burden of VTE in cancer patients, discussing the performance of available risk assessment scores, and summarizing the findings of recent trials. This overview can help oncologists, hematologists, and vascular medicine specialists decide about thromboprophylaxis in ambulatory cancer patients.
Project description:Several Western guidelines recommend the routine use of pharmacologic thromboprophylaxis for cancer surgery patients to prevent venous thromboembolism (VTE). However, the necessity of routine pharmacologic perioperative thromboprophylaxis in Asian gastric cancer (GC) patients has not been clearly determined. To determine the necessity of routine perioperative pharmacologic thromboprophylaxis in Korean gastric cancer patients, the incidence of postoperative VTE was prospectively evaluated in gastric cancer patients receiving surgery. Among 610 GC patients who had received surgery, 375 patents underwent routine duplex Doppler ultrasonography (DUS) on days 5-12 following surgery to detect VTE and then VTE-related symptoms and signs were checked at 4 weeks after surgery (cohort A). The 235 patients that declined DUS were registered to cohort B and the occurrence of postoperative VTE was retrospectively analyzed. In cohort A, symptomatic or asymptomatic VTE until 4 weeks after surgery was detected in 9 patients [2.4%; 95% confidence interval (CI); 0.9-3.9]. Tumor stage was a significant factor related to VTE development [stage I, 1.4%; stage II/III, 2.4%; stage IV, 9.7% (P = 0.008)]. In multivariate analysis, patients with stage IV had a higher postoperative VTE development [odds ratio, 8.18 (95% CI, 1.54-43.42)] than those with stage I. In cohort B, a low incidence of postoperative VTE was reaffirmed; only one postoperative VTE case (0.4%) was observed. In conclusion, the incidence of postoperative VTE in Korean GC patients was only 2.4%. Risk-stratified applications of perioperative pharmacologic thromboprophylaxis are thought to be more appropriate than the routine pharmacologic thromboprophylaxis in Korean GC patients receiving surgery.
Project description:Venous thromboembolism (VTE) is a common cause of morbidity and mortality among patients with multiple myeloma (MM). The International Myeloma Working Group (IMWG) developed guidelines recommending primary thromboprophylaxis, in those identified at high-risk of VTE by the presence of risk factors. The National Comprehensive Cancer Network (NCCN) has adopted these guidelines; however, they lack validation. We sought to develop and validate a risk prediction score for VTE in MM and to evaluate the performance of the current IMWG/NCCN guidelines. Using 4446 patients within the Veterans Administration Central Cancer Registry, we used time-to-event analyses to develop a risk score for VTE in patients with newly diagnosed MM starting chemotherapy. We externally validated the score using the Surveillance, Epidemiology, End Results (SEER)-Medicare database (N = 4256). After identifying independent predictors of VTE, we combined the variables to develop the IMPEDE VTE score (Immunomodulatory agent; Body Mass Index ?25?kg/m2 ; Pelvic, hip or femur fracture; Erythropoietin stimulating agent; Dexamethasone/Doxorubicin; Asian Ethnicity/Race; VTE history; Tunneled line/central venous catheter; Existing thromboprophylaxis). The score showed satisfactory discrimination in the derivation cohort, c-statistic = 0.66. Risk of VTE significantly increased as score increased (hazard ratio 1.20, P =?<.0001). Within the external validation cohort, IMPEDE VTE had a c-statistic of 0.64. For comparison, when evaluating the performance of the IMWG/NCCN guidelines, the c-statistic was 0.55. In summary, the IMPEDE VTE score outperformed the current IMWG/NCCN guidelines and could be considered as the new standard risk stratification for VTE in MM.
Project description:Patients with cancer are at increased risk for venous thromboembolism (VTE). Factors related to cancer type, site, stage, duration, and extent of disease contribute to the oncology patient's risk of VTE. Patient-specific factors such as history of prior VTE and comorbidity are also contributory. The role of treatment-related factors, including chemotherapy regimen, has been a focus of recent investigation because most cases of VTE in the oncology setting occur in ambulatory patients. Thus, an emerging area of clinical research is primary VTE prophylaxis in the ambulatory cancer setting. Clinical guidelines currently recommend primary thromboprophylaxis in cancer patients who are undergoing surgery, who are hospitalized, and who are in a specific subset of high-risk ambulatory cancer patients. Validated risk stratification tools are essential for identification of patients who are at high risk of thrombosis. Emerging data from recently published clinical trials, as well as ongoing studies, are likely to advance our understanding of the potential utility of antithrombotic agents for primary prophylaxis in ambulatory patients with cancer and may influence future clinical guideline recommendations.
Project description:BACKGROUND:Venous thromboembolism (VTE) is a leading cause of death among patients with cancer. Outpatients with cancer should be periodically assessed for VTE risk, for which the Khorana score is commonly recommended. However, it has been questioned whether this tool is sufficiently accurate at identifying patients who should receive thromboprophylaxis. The present work proposes a new index, TiC-Onco risk score to be calculated at the time of diagnosis of cancer, that examines patients' clinical and genetic risk factors for thrombosis. METHODS:We included 391 outpatients with a recent diagnosis of cancer and candidates for systemic outpatient chemotherapy. All were treated according to standard guidelines. The study population was monitored for 6 months, and VTEs were recorded. The Khorana and the TiC-Onco scores were calculated for each patient and their VTE predictive accuracy VTEs was compared. RESULTS:We recorded 71 VTEs. The TiC-Onco risk score was significantly better at predicting VTE than the Khorana score (AUC 0.73 vs. 0.58, sensitivity 49 vs. 22%, specificity 81 vs. 82%, PPV 37 vs. 22%, and NPV 88 vs. 82%). CONCLUSIONS:TiC-Onco risk score performed significantly better than Khorana score at identifying cancer patients at high risk of VTE who would benefit from personalised thromboprophylaxis.
Project description:BACKGROUND:Preliminary evidence indicates that prophylactic-dose thromboprophylaxis may be inadequate to control the increased risk of venous thromboembolism (VTE) in patients hospitalized for coronavirus disease 2019 (COVID-19) infection. Additionally, it remains unclear whether the D-dimer measurement is useful for VTE risk stratification among COVID-19 patients. This study aimed to offer benchmark data on the incidence of VTE and to examine the difference in D-dimer levels among anticoagulated COVID-19 patients with and without VTE incident. METHODS:A comprehensive literature review of PubMed from inception to May 2020 was performed for original studies that reported the frequency of VTE and death among COVID-19 patients who received thromboprophylaxis on hospitalization. The endpoints included VTE (a composite of pulmonary embolism (PE) or deep vein thrombosis (DVT)), PE, DVT, and mortality. RESULTS:A total of 11 cohort studies were included. Among hospitalized COVID-19 patients, 23.9% (95% confidence interval (CI), 16.2% to 33.7%; I2 = 93%) developed VTE despite anticoagulation. PE and DVT were detected in 11.6% (95% CI, 7.5% to 17.5%; I2 = 92%) and 11.9% (95% CI, 6.3% to 21.3%; I2 = 93%) of patients, respectively. Patients in the intensive care unit (ICU) had a higher risk for VTE (30.4% )95% CI, 19.6% to 43.9%)) than those in the ward (13.0% (95% CI, 5.9% to 26.3%)). The mortality was estimated at 21.3% (95% CI, 17.0% to 26.4%; I2 = 53%). COVID-19 patients who developed VTE had higher D-dimer levels than those who did not develop VTE (mean difference, 2.05 µg/mL; 95% CI, 0.30 to 3.80 µg/mL; P = 0.02). CONCLUSIONS:The heightened and heterogeneous risk of VTE in COVID-19 despite prophylactic anticoagulation calls into research on the pathogenesis of thromboembolic complications and strategy of thromboprophylaxis and risk stratification. Prominent elevation of D-dimer may be associated with VTE development and can be used to identify high-risk subsets.
Project description:BACKGROUND:Thromboprophylaxis for patients with non-surgical isolated lower-limb trauma requiring immobilization is a matter of debate. Our aim was to develop and validate a clinical risk- stratification model based on Trauma, Immobilization and Patients' characteristics (the TIP score). METHODS:The TIP score criteria and the cut-off were selected by a consensus of international experts (n = 27) using the Delphi method. Retrospective validation was performed in a population-based case-control study (MEGA study). The potential score's impact in anticoagulant treatment was assessed in a prospective single-center observational cohort study. FINDINGS:After four successive rounds, 30 items constituting the TIP score were selected: thirteen items for trauma, three for immobilization and 14 for patient characteristics were selected, each rated on a scale of 1 to 3. In the validation database, the TIP score had an AUC of 0·77 (95% CI 0.70 to 0.85). Using the cut-off proposed by the experts (?5) and assuming a prevalence of 1·8%, the TIP scores had a sensitivity, specificity and negative predictive values of 89·9%, 30·7% and 99·4% respectively. In the prospective cohort, 84·2% (165/196) of all the patients concerned who presented at the emergency department had a low VTE risk not requiring thromboprophylaxis according to their TIP scores. The 3-month rate of symptomatic VTE was 1/196 [95% CI 0.1-2.8] this patient was in the sub-group TIP score ?5. CONCLUSION:For patients with non-surgical lower-limb trauma and orthopedic immobilization, the TIP score allows an individual VTE risk-assessment and shows promising results in guiding thromboprophylaxis.
Project description:Background:Clinical practice shows that venous thromboembolism (VTE) presents a substantial burden in medical patients, and awareness and advocacy for its primary and secondary prevention remains inadequate. Specific patient populations, such as those with cancer and the critically ill, show elevated risk for VTE, bleeding or both, and significant gaps in VTE prophylaxis and treatment exist in these groups. Objective:To present novel insights and consolidated evidence collected from experts, clinical practice guidelines and original studies on the unmet needs in thromboprophylaxis, and on the treatment of VTE in two high-risk patient groups: patients with cancer and the critically ill. Methodology:To identify specific unmet needs in the management of VTE, a methodology was designed and implemented that assessed gaps in prophylaxis and treatment of VTE through interviews with 44 experts in the field of thrombosis and haemostasis, and through a review of current guidelines and seminal studies to substantiate the insights provided by the experts. The research findings were then analysed, discussed and consolidated by a multidisciplinary group of experts. Results:The gap analysis methodology identified shortcomings in the VTE risk assessment tools, patient stratification approaches for prophylaxis, and the suboptimal use of anticoagulants for primary prophylaxis and treatment. Conclusions:Specifically, patients with cancer need better VTE risk assessment tools to tailor primary thromboprophylaxis to tumour types and disease stages, and the potential for drug-drug interactions needs to be considered. In critically ill patients, unfractionated heparin is not advised as a first-line treatment option, and the strength of evidence is increasing for direct oral anticoagulants as a treatment option over low-molecular-weight heparins.
Project description:Pharmacologic thromboprophylaxis is routinely recommended for Western cancer patients undergoing major surgery for prevention of venous thromboembolism (VTE). However, it is uncertainwhetherroutine administration of pharmacologic thromboprophylaxis is necessary in all Asian surgical cancer patients. This prospective study was conducted to examine the incidence of and risk factors for postoperative VTE in Korean colorectal cancer (CRC) patients undergoing major abdominal surgery.This study comprised two cohorts, and none of patients received perioperative pharmacologic thromboprophylaxis. In cohort A (n=400), patients were routinely screened for VTE using lower-extremity Doppler ultrasonography (DUS) on postoperative days 5-14. In cohort B (n=148), routine DUS was not performed, and imaging was only performed when there were symptoms or signs that were suspicious for VTE. The primary endpoint was the VTE incidence at 4 weeks postoperatively in cohort A.The postoperative incidence of VTE was 3.0% (n=12) in cohort A. Among the 12 patients, eight had distal calf vein thromboses and one had symptomatic thrombosis. Age ? 70 years (odds ratio [OR], 5.61), ? 2 comorbidities (OR, 13.42), and white blood cell counts of > 10,000/?L (OR, 17.43) were independent risk factors for postoperative VTE (p < 0.05). In cohort B, there was one case of VTE (0.7%).The postoperative incidence of VTE, which included asymptomatic cases, was 3.0% in Korean CRC patients who did not receive pharmacologic thromboprophylaxis. Perioperative pharmacologic thromboprophylaxis should be administered to Asian CRC patients on a risk-stratified basis.