Risk Of Cancer-associated Thrombosis Research Articles

Evaluation of Clinical Risk Factors and Thrombosis-Related Biomarkers in Newly Diagnosed Patients with Multiple Myeloma at Risk for Cancer-Associated Thrombosis. the Observational Roadmat-CAT-MM Study

Background: Hypercoagulability is a common blood alteration in newly diagnosed chemotherapy naïve patients with multiple myeloma. Multiple myeloma (MM) figures among malignancies that significantly increase the risk of venous thromboembolism (VTE). The rate of VTE is higher at the time of diagnosis and during the first months following initiation of first line therapy; approximately 10% of newly diagnosed MM (NDMM) will develop a VTE. Despite adequate thromboprophylaxis as per guidelines, the risk of residual VTE is not eliminated and remains as high as 12%. The optimization of VTE prevention in patients with MM is an unmet need. The exact mechanism of the increased risk of VTE is not yet fully understood. The identification of the procoagulant potential of cancer cells, which is related principally to tissue factor (TF) expression, attracts particular interest. Aim: We conducted a longitudinal prospective observational study, to explore the relationship of MM with cellular and plasma hypercoagulability as well as tissue factor positive microparticles, aiming to identify the most relevant biomarkers, which could be used in a Risk Assessment Model (RAM) for VTE in combination with clinical risk factors. Methods: Newly diagnosed patients (182) with multiple myeloma (NDMM) were prospectively enrolled. Patients were followed up for 12 months and the primary end-point was symptomatic objectively confirmed VTE. Patients were risk stratified and received thromboprophylaxis (none, aspirin on low molecular weight heparin (LMWH) based on previously published recommendations by the IMWG and EMN. Prior to treatment initiation and thromboprophylaxis initiation baseline biomarkers were obtained: Thrombin generation (TGT) in citrated PPP was assessed with the Thrombogram-Thrombinoscope® assay using PPP-reagent® 5 pm TF by Diagnostica Stago. The levels of P-Selectin and heparanase in plasma were measured with ELISA Kit (Cusabio Biotech and R&D Systems respectively). The procoagulant phospholipids clotting time was measured with STA-Procoag-PPL®, Levels of Factor VIIa were measured by Staclot VIIa-rTF®, D-Dimers (DDi) by Liatest D-Di (Diagnostica Stago, France), and Tissue Factor activity (TFa) by specific clotting based home test. TF expression MPC-derived microparticles (MPC-dMPs) were detected using a Zymuphen MP-TF activity kit (Hyphen BioMed, Neuville sur Oise, France). These were compared against values in a population of healthy individuals (n=30). Results: The distribution of patients enrolled in the study is as follows: Median age was 67 years (36-86) and 52% of the population was male. Median time to follow up was 7 months (1-12 months). The control group (30 healthy individuals). The overall rate of symptomatic VTE during follow-up was 11.5% (n = 21 patients). Eleven out of 21 events (52%) occurred within 3 months from treatment initiation. Six of these patients did not receive any thromboprophylaxis; six patients were on aspirin at the time of the event and three were on LMWH.At inclusion, patients showed significantly increased levels of TFa, FVIIa, D-Dimers and FM, and significantly shorter Procoag-PPL® as compared to the group of healthy individuals. Levels of P-selectin and TM were significantly lower in patients as compared to healthy individuals. The levels of heparanase were not significantly different in the group of patients as compared to the healthy individuals. Overall thrombin generation was attenuated in patients compared to healthy individuals. Lag-time and ttPeak were significantly increased and Peak, MRI, and ETP were significantly lower as compared to the control group, MP-TF activity measured in NDMM significantly increased 1.46± 0.38 pg/mL compared to control subjects 0.19 ± 0.05 pg/mL (Table 1). Multivariate logistic regression analysis demonstrated that ETP, Procoag-PPL® and MP-TF were independently associated with VTE occurrence. (Table 2) Conclusion: The prospective ROADMAP-CAT-MM study demonstrates the presence of pronounced cellular hypercoagulability in newly diagnosed chemotherapy naïve patients with MM characterized by decreased Procoag-PPL® clotting time, enhanced endothelial cell activation, and exhausted thrombin generation. The Procoag-PPL clotting time and the ETP and MP-TF were found to be independently associated with the risk of VTE and can be prospectively incorporated into a RAM for VTE in MM.

Epidemiology of Cancer-Associated Venous Thromboembolism in Patients With Solid and Hematologic Neoplasms in the Veterans Affairs Health Care System

Identifying changes in epidemiologic patterns of the incidence and risk of cancer-associated thrombosis (CAT), particularly with evolving cancer-directed therapy, is essential for risk stratification. To assess the incidence of CAT over time and to determine pertinent patient-specific, cancer-specific, and treatment-specific factors associated with its risk. This longitudinal, retrospective cohort study was conducted from 2006 to 2021. Duration of follow-up was from the date of diagnosis until first venous thromboembolism (VTE) event, death, loss of follow-up (defined as a 90-day gap without clinical encounters), or administrative censoring on April 1, 2022. The study took place within the US Department of Veterans Affairs national health care system. Patients with newly diagnosed invasive solid tumors and hematologic neoplasms were included in the study. Data were analyzed from December 2022 to February 2023. Newly diagnosed invasive solid tumors and hematologic neoplasms. Incidence of VTE was assessed using a combination of International Classification of Diseases, Ninth Revision, Clinical Modification and International Statistical Classification of Diseases, Tenth Revision, Clinical Modification and natural language processing confirmed outcomes. Cumulative incidence competing risk functions were used to estimate incidence of CAT. Multivariable Cox regression models were built to assess the association of baseline variables with CAT. Pertinent patient variables included demographics, region, rurality, area deprivation index, National Cancer Institute comorbidity index, cancer type, staging, first-line systemic treatment within 3 months (time-varying covariate), and other factors that could be associated with the risk of VTE. A total of 434 203 patients (420 244 men [96.8%]; median [IQR] age, 67 [62-74] years; 7414 Asian or Pacific Islander patients [1.7%]; 20 193 Hispanic patients [4.7%]; 89 371 non-Hispanic Black patients [20.6%]; 313 157 non-Hispanic White patients [72.1%]) met the inclusion criteria. Overall incidence of CAT at 12 months was 4.5%, with yearly trends ranging stably from 4.2% to 4.7%. The risk of VTE was associated with cancer type and stage. In addition to confirming well-known risk distribution among patients with solid tumors, a higher risk of VTE was observed among patients with aggressive lymphoid neoplasms compared with patients with indolent lymphoid or myeloid hematologic neoplasms. Compared with no treatment, patients receiving first-line chemotherapy (hazard ratio [HR], 1.44; 95% CI, 1.40-1.49) and immune checkpoint inhibitors (HR, 1.49; 95% CI, 1.22-1.82) had a higher adjusted relative risk than patients receiving targeted therapy (HR, 1.21; 95% CI, 1.13-1.30) or endocrine therapy (HR, 1.20; 95% CI, 1.12-1.28). Finally, adjusted VTE risk was significantly higher among Non-Hispanic Black patients (HR, 1.23; 95% CI, 1.19-1.27) and significantly lower in Asian or Pacific Islander patients (HR, 0.84; 95% CI, 0.76-0.93) compared with Non-Hispanic White patients. In this cohort study of patients with cancer, a high incidence of VTE was observed, with yearly trends that remained stable over the 16-year study period. Both novel and known factors associated with the risk of CAT were identified, providing valuable and applicable insights in this current treatment landscape.

PAD4 and Its Inhibitors in Cancer Progression and Prognosis.

The systemic spread of malignancies and the risk of cancer-associated thrombosis are major clinical challenges in cancer therapy worldwide. As an important post-translational modification enzyme, peptidyl arginine deiminase 4 (PAD4) could mediate the citrullination of protein in different components (including nucleus and cytoplasm, etc.) of a variety of cells (tumor cells, neutrophils, macrophages, etc.), thus participating in gene regulation, neutrophil extracellular trap (NET) and macrophage extracellular trap (MET). Thereby, PAD4 plays an important role in enhancing the growth of primary tumors and facilitating the distant metastasis of cancer cells. In addition, it is related to the formation of cancer-associated thrombosis. Therefore, the development of PAD4-specific inhibitors may be a promising strategy for treating cancer, and it may improve patient prognosis. In this review, we describe PAD4 involvement in gene regulation, protein citrullination, and NET formation. We also discuss its potential role in cancer and cancer-associated thrombosis, and we summarize the development and application of PAD4 inhibitors.

Procoagulant Phospholipid Dependent Clotting Time: A New Tool for the Identification of Multiple Myeloma Patients at Risk Poor Treatment Response

Background: Research has long focused on the implications of platelet, endothelial cell and blood coagulation activation in the risk of venous thromboembolism in patients with multiple myeloma (MM). Given the pivotal role of the malignant cell in coagulation activation we studied the association between biomarkers of hypercoagulability and cancer cell activity.Aim: Using data from the prospective, longitudinal observational study ROADMAP-MM CAT (PROspective Risk Assessment anD bioMArkers of hyPercoagulability for the identification of patients with Multiple Myeloma at risk for Cancer Associated Thrombosis) we aimed to identify biomarkers of cellular and plasma hypercoagulability that play a role in determining response to the anti-myeloma treatment.Methods: Newly diagnosed patients with MM were enrolled. Patients on anticoagulant treatment were excluded. A standardized clinical research form (CRF) was completed at enrollment (T0) and at 3 months post treatment initiation (T1). Blood samples were collected at the same time points. Procoagulant phospholipid-dependent clotting time (Procoag-PPL®), tissue factor activity (TFa), thrombomodulin activity (TMa), factor VIIa, factor V (FV), antithrombin (AT), fibrin monomers (FM) and D-Dimers were measured with respective assays from Diagnostica Stago (Asnieres, France) on a STA-R® analyzer (Diagnostica Stago). Plasma levels of P-Selectin and heparanase were measured with ELISA Kits from Cusabio Biotech (from CliniSciencies, France) and R&D Systems (Lille France), respectively. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5pMPPP-Reagent® on Calibrated Automated Thrombogram (Stago, France). The control group (CG) consisted of 30 healthy age and sex-matched individuals.Results. A total of 100 treatment naïve MM patients were enrolled. Median age was 66.5±12.0 (37-88) years and 54% of the population was male. Disease stage was distributed as follows: 24.3% ISS-I, 20.4% ISS II and 55.3% ISS-III. Bortezomib-based therapy was given to 64.1% of the patients, thalidomide based in 6.8% and lenalidomide-based in 24.3%. Median time to follow up was 11.5 months. There were 16 deaths overall and mortality rate was 162/1000 person-years (median time of death since diagnosis 4.5 months, range 1-9 months). At T1, patients with stable disease (n=8) and progressive disease (n=14) were classified as non-responders. A total of 78 patients achieved at least a partial response and were classified as responders. Compared to controls at T0, MM patients showed significantly increased levels of TFa, D-Dimers and FM and significantly shorter Procoag-PPL clotting time. P-selectin levels were significantly decreased and heparanase levels significantly increased. FVIIa, FV and AT were not significantly different between patients and controls. MM patients showed significantly increased lag-time and ttPeak and significantly lower Peak, ETP and MRI as compared to the control group. TFa and D-dimer levels decreased significantly 3 months post treatment initiation (T1) whereas TMa and AT significantly decreased. At T1 thrombin generation was further attenuated (lower ETP and Peak, prolongation of ttPeak and lower MRI). Univariate analysis demonstrated that among the studied biomarkers only short PPL-ct was associated with a significantly increased risk of no response to treatment. The area under the curve (AUC) in a plot of PPL-ct against no response to treatment (receiver operator curve analysis) was 0.7 (p=0.01).Conclusion. The prospective ROADMAP-CAT multiple myeloma study demonstrates for the first time that among a large number of hypercoagulability biomarkers assessed in newly diagnosed treatment-naïve MM patients, PPL-ct, that reflects the amount of procoagulant microparticles present in plasma, is a significant predictor of poor treatment response. A prospective trial is required to evaluate the potential role of this biomarker in anti-myeloma treatment optimization. [Display omitted] DisclosuresTerpos:Amgen: Honoraria, Other: SC member, Research Funding; Takeda: Honoraria, Other: SC member, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Abbvie: Honoraria; GSK: Honoraria. Garderet:Takeda: Honoraria; Amgen: Honoraria.

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Patients with Lung Adenocarcinoma at Risk for Cancer Associated Thrombosis. the Observational Roadmap-CAT Study

INTRODUCTION: The aim of this prospective longitudinal study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE).METHODS: 150 ambulatory patients with lung adenocarcinoma were prospectively enrolled as well as a control group comprised of 30 healthy age & sex-matched individuals. Thrombin generation parameters, procoagulant phospholipid-dependent clotting time (Procoag-PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin (AT), D-Dimers (DDi), P-selectin and heparanase levels were assessed in platelet-poor plasma (PPP) at inclusion (baseline) and at the end of the 3rd chemotherapy cycle (acute phase). Cox regression analysis was used to identify independent VTE predictors.RESULTS: At baseline, patients had significantly attenuated thrombin generation, shorter Procoag-PPL, higher levels of TFa, D-Dimers and heparanase, and lower levels of FVIIa and P-selectin, compared to controls. A significant increase in Procoag-PPL, FV and FVIIa and a decrease of P-selectin levels was observed between baseline and the acute phase. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index of thrombin generation (MRI) and Procoag-PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including the above parameters had improved discriminating capacity (area under the curve/AUC: 0.84).CONCLUSIONS: Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag-PPL, increased endothelial cell activation and increased degradation of fibrin. Incorporation of Procoag-PPL and MRI of thrombin generation may improve the accuracy of a VTE RAM in the above setting. DisclosuresNo relevant conflicts of interest to declare.

Genes and proteins associated with the risk for cancer-associated thrombosis

Cancer patients have a four- to sevenfold increased risk of developing cancer-associated thrombosis (CAT), which is associated with a strong increase in morbidity and mortality. Not all cancer patients receive thromboprophylaxis as this may lead to adverse events in a cancer population that is already at increased risk for major bleedings. Different risk prediction models have been developed to identify cancer patients at high risk of developing CAT that may be selected for thromboprophylaxis. However, risk models using the currently established biomarkers and clinical parameters perform poorly, particularly when validated in independent cohorts. Discovery of new and better biomarkers are therefore urgently needed. This review describes how aberrations in the genetic profile of the tumor and host influence a hypercoagulable state, and explores how these can be used as novel biomarker to improve CAT risk prediction.

In Newly Diagnosed Multiple Myeloma Patients, Longer Procoagulant Phospholipid-Dependent Clotting Time, Higher Levels of P-Selectin, D-Dimers and Thrombin Generation Peak Are Associated with Increased Risk of Resistance to Treatment: Results of the Prospective Roadmap-MM Study

Background:Despite an increasing number of approved therapies, multiple myeloma (MM) remains an incurable disease with frequent drug resistsance. Resistance-mediating alterations are preexisting in early disease, and it is the selective pressure of antitumor therapy that promotes their clonal expansion from baseline tumor heterogeneity. Cross-talk between monoclonal plasma cells, platelets and endothelial cells enhances hypercoagulability. The prospective, longitudinal observational study ROADMAP-MM CAT (PROspective Risk Assessment anD bioMArkers of hyPercoagulability for the identification of patients with Multiple Myeloma at risk for Cancer Associated Thrombosis) was designed to explore alternative strategies for the development of risk stratification tools in patients with MM. Aim: We explored cellular and plasma hypercoagulability in newly diagnosed chemotherapy naïve MM (NDMM) patients to identify relevant biomarkers that can be used to classify patients at high risk of resistance to anti-myeloma treatment. Methods: Symptomatic NDMM were enrolled. Patients on anticoagulant treatment were excluded from the study. Study end-point was response to treatment at 3 months (T1) according the the International Myeloma Working Group response criteria. “Resistance to antimyeloma treatment” was defined as progressive disease (PD), stable disease (SD) or minor response (MR) at 3 months post treatment initiation. Blood samples were collected at inclusion. Procoagulant phospholipid-dependent clotting time (Procoag-PPL®), tissue factor activity (TFa), thrombomodulin activity (TMa), factor VIIa, factor V (FV), antithrombin (AT), fibrin monomers (FM) and D-Dimers were measured with respective assays from Diagnostica Stago (Asnieres, France) on a STA-R® analyzer (Diagnostica Stago). Plasma levels of P-Selectin and heparanase were measured with ELISA Kits from Cusabio Biotech (from CliniSciencies, France) and R&D Systems (Lille France), respectively. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5 pM PPP-Reagent® on Calibrated Automated Thrombogram (Stago, France). Univariate logistic regression analysis examined the associations between biomarkers and treatment resistance. The cut-off values for studied biomarkers were selected based on ROC analysis. Results A total of 144 patients were enrolled (age 66.0±12.0 yrs; 53% male). Distribution of disease stage was as follows: 32% ISS I, 23% ISS II, 45% ISS III. Bone disease was present in 71% of patients and 19% of patients had high risk cytogenetic lesions. Proteasome inhibitor (PI) based therapy was given to 64% of patients, immunomodulatory drug (IMiD) based therapy in 32% and 4% received other regimens. At 3 months, 64% of patients showed treatment “resistance”. At the univariate logistic regression “resistance to treatment” was associated with longer Procoag-PPL (32.4% in patients with Procoag-PPL ≥41.7 sec vs. 12.3% in patients with Procoag-PPL <41.7 sec; OR=3.41, 95%CI: 1.45-8.03, p=0.005), higher levels of D-dimers (36.0% in patients with D-dimers ≥1.44 μg/ml vs. 14.9% in patients with D-dimers <1.44 μg/ml; OR=3.21, 95%CI: 1.43-7.22, p=0.005) and higher Peak in the thrombogram (28.1% in patients with Peak ≥181.66 nM vs. 12.5% in patients with Peak <181.66 nM; OR=2.73, 95%CI: 1.03-7.23, p=0.043). On the other hand, PD/SD/MR rate was inversely associated with P-selectin levels (14.5% in patients with ≥23477 pg/ml vs. 42.3% in patients with P-selectin <23477 pg/ml; OR=0.23, 95%CI: 0.08-0.65, p=0.005). Conclusion. The prospective ROADMAP-CAT multiple myeloma study demonstrates for the first time that biomarkers of hypercoagulablity may also be useful to identify patients likely to display resistance to treatment. Among a large number of hypercoagulability biomarkers PPL-ct, that reflects the amount of procoagulant microparticles present in plasma, thrombin generation and the levels P-Selectine and D-Dimers were found to be significant predictors of poor treatment response. A prospective trial is required to evaluate the potential role of these biomarkers in anti-myeloma treatment optimization. DisclosuresTerpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Dimopoulos:Celgene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria.

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Newly Diagnosed Chemotherapy Naïve Patients with Multiple Myeloma at Risk for Cancer-Associated Thrombosis. The Observational ROADMAT-CAT-MM Study

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Newly Diagnosed Chemotherapy Naïve Patients with Multiple Myeloma at Risk for Cancer-Associated Thrombosis. The Observational ROADMAT-CAT-MM Study

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Patients with Lung Adenocarcinoma at Risk for Cancer-Associated Thrombosis: The Observational ROADMAP-CAT Study.

The aim of this prospective study was to identify the most clinically relevant hypercoagulability biomarkers in lung adenocarcinoma patients for elaboration of an improved risk assessment model (RAM) for venous thromboembolism (VTE). One hundred fifty ambulatory patients with lung adenocarcinoma were prospectively enrolled. Thrombin generation, procoagulant phospholipid-dependent clotting time (Procoag-PPL), tissue factor activity (TFa), factor VIIa (FVIIa), factor V (FV), antithrombin, D-Dimers, P-selectin, and heparanase levels were assessed in platelet-poor plasma at inclusion (baseline) and at the end of the third chemotherapy cycle (third chemotherapy). Cox regression analysis was used to identify independent VTE predictors. At baseline, patients had significantly attenuated thrombin generation, shorter Procoag-PPL, higher levels of TFa, D-Dimers, and heparanase, and lower levels of FVIIa and P-selectin, compared with controls. A significant increase in Procoag-PPL, FV, and FVIIa and a decrease of P-selectin levels were observed between baseline and third chemotherapy. Hospitalization within the last 3 months prior to assessment, time since cancer diagnosis less than 6 months, mean rate index (MRI) of thrombin generation, and Procoag-PPL were independently associated with symptomatic VTE. Accordingly, a prediction model including Procoag-PPL and MRI showed significant discriminating capacity (area under the curve: 0.84). Ambulatory patients with lung adenocarcinoma may display pronounced blood hypercoagulability due to decreased Procoag-PPL, increased endothelial cell activation, and increased degradation of fibrin. Incorporation of Procoag-PPL and MRI of thrombin generation may improve the accuracy of a VTE-RAM in the above setting. The prospective ROADMAP-CAT study identified two biomarkers of hypercoagulability, the procoagulant phospholipid-dependent clotting time (Procoag-PPL) and the mean rate index (MRI) of the propagation phase of thrombin generation assessed with the Calibrated Automated Thrombinoscope, as being clinically relevant for the classification of ambulatory patients with lung adenocarcinoma receiving a maximum of one cycle of chemotherapy into high and intermediate/low risk for venous thromboembolism. Measurement of Procoag-PPL and MRI within 1 month after the administration of the first chemotherapy cycle provides significant accuracy of the assessment. Association of the Procoag-PPL and MRI with the clinical risk assessment model for cancer-associated thrombosis in ambulatory patients with solid tumors (COMPASS-CAT RAM) further improved its accuracy.

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Newly diagnosed chemotherapy Naïve Patients with Multiple Myeloma at Risk for Cancer-associated Thrombosis. The Observational ROADMAP-CAT-MM Study

Prospective Assessment of Clinical Risk Factors and Biomarkers of Hypercoagulability for the Identification of Newly diagnosed chemotherapy Naïve Patients with Multiple Myeloma at Risk for Cancer-associated Thrombosis. The Observational ROADMAP-CAT-MM Study

Do circulating tumor cells play a role in coagulation and thrombosis?

Cancer induces a hypercoagulable state, and patients with cancer who suffer a thrombotic event have a worse prognosis than those who do not. Recurrent pathologic thrombi in patients with cancer are clinically managed with anticoagulant medications; however, anticoagulant prophylaxis is not routinely prescribed owing to a complex variety of patient and diagnosis related factors. Early identification of patients at risk for cancer-associated thrombosis would allow for personalization of anticoagulant prophylaxis and likely reduce morbidity and mortality for many cancers. The environment in which a thrombosis develops in a patient with cancer is complex and unique from patients without cancer, which creates therapeutic challenges but may also provide targets for the development of clinical assays in this context. Circulating tumor cells (CTCs) may play a role in the association between cancer and thrombosis. Cancer metastasis, the leading cause of cancer-related deaths, is facilitated by the hematogenous spread of CTCs, and CTCs accompany metastatic disease across all major types of carcinomas. The role of CTCs in the pathogenesis of thrombosis has not been studied due to the previous difficulty in identifying these rare cells, but the interaction between these circulating cells and the coagulation system is an area of study that demands attention. The development of CTC detection platforms presents a new tool by which to characterize the role for CTCs in cancer-related hypercoagulability. In addition, this area of study presents a new avenue for assessing the risk of cancer-associated thrombosis and represents a potential tool for predicting which patients may benefit from anticoagulant prophylaxis. In this review, we will discuss the evidence in support of CTC induced hypercoagulability, and highlight areas where CTC-detection platforms may provide prognostic insight into the risk of developing thrombosis for patients with cancer.

Treatment of Cancer-Associated Thrombosis: Distinguishing Among Antithrombotic Agents

The risk of cancer-associated thrombosis can be substantial, depending on tumor type, extent of cancer, and type of treatment. Unfractionated heparin and warfarin have been used in the prevention of cancer-associated thrombosis, but low-molecular-weight heparin (LMWH) is widely used for the prevention of venous thromboembolism in high-risk patients. Long-term management with warfarin is associated with close monitoring, an increased risk of drug interactions, and bleeding. LMWHs may offer an alternative outpatient treatment strategy for prophylactic treatment because of their simpler dosing, more predictable anticoagulant activity, and improved safety profile. Clinical trials examining the treatment of venous thromboembolism with LMWH in patients with cancer suggest a survival advantage for the treated groups. Subtle differences in the pharmacokinetics of available LMWHs exist, and each LMWH should be regarded as a distinct drug. Pharmacists should be aware of the US Food and Drug Administration-approved uses for each LMWH, dosing options, and the advantages and disadvantages of available delivery systems for various patient populations. Pharmacists can play a major role in educating patients and other health care professionals on risk factor recognition, patient risk stratification, and proper agent selection for prevention and treatment of cancer-associated thrombosis.

Low-Molecular-Weight Heparins in the Treatment of Cancer-Associated Thrombosis: A New Standard of Care?

Cancer patients are twice as likely to develop postoperative venous thromboembolism (VTE) than non-cancer patients undergoing the same surgical procedure. Causes of cancer-associated thrombosis include: the capacity of tumor cells and their products to interact with platelets, clotting, and fibrinolytic proteins. Aggressive antitumor therapy with agents such as platinum compounds, high-dose fluorouracil, mitomycin-C, tamoxifen, and growth factors increase the risk of cancer-associated thrombosis. Despite the high risk of VTE in patients with cancer, thromboprophylaxis in surgical and medical oncology patients is low. Initial therapy of VTE in patients with cancer is low-molecular-weight heparin (LMWH) or unfractionated heparin. Long-term secondary prophylaxis of VTE is generally accomplished with oral anticoagulants, primarily warfarin. Evidence supports the use of LMWH for prevention and treatment of cancer-associated thrombosis because it is more easily administered, does not require laboratory monitoring, has a lower risk of adverse events, and is more cost effective than unfractionated heparin. In addition, the antineoplastic effects of LMWH have been demonstrated, including direct antitumor, antiangiogenic, and immune system modulatory action. Each LMWH is a unique biological entity having product-specific molecular and structural attributes; therefore, different LMWHs cannot be given interchangeably. Continued investigation of LMWH therapy in patients with cancer is warranted.