Anticoagulation in cancer-associated thromboembolism with thrombocytopenia: a prospective, multicenter cohort study.

Venous thromboembolism (VTE) with concurrent thrombocytopenia is frequently encountered in patients with cancer. Therapeutic anticoagulation in the setting of thrombocytopenia is associated with a high risk of hemorrhage. Retrospective analyses suggest the utility of modified-dose anticoagulation in this population. To assess the incidence of hemorrhage or thrombosis according to anticoagulation strategy, we performed a prospective, multicenter, observational study. Patients with active malignancy, acute VTE, and concurrent thrombocytopenia (platelet count <100 000/µL) were enrolled. The cumulative incidences of hemorrhage or recurrent VTE were determined considering death as a competing risk. Primary outcomes were centrally adjudicated and comparisons made according to initial treatment with full-dose or modified-dose anticoagulation. A total of 121 patients were enrolled at 6 hospitals. Seventy-five patients were initially treated with full-dose anticoagulation (62%) and 33 (27%) with modified-dose anticoagulation; 13 (11%) patients received no anticoagulation. Most patients who received modified-dose anticoagulation had a hematologic malignancy (31 of 33 [94%]) and an acute deep vein thrombosis (28 of 33 [85%]). In patients who initially received full-dose anticoagulation, the cumulative incidence of major hemorrhage at 60 days was 12.8% (95% confidence interval [CI], 4.9-20.8) and 6.6% (95% CI, 2.4-15.7) in those who received modified-dose anticoagulation (Fine-Gray hazard ratio, 2.18; 95% CI, 1.21-3.93). The cumulative incidence of recurrent VTE at 60 days in patients who initially received full-dose anticoagulation was 5.6% (95% CI, 0.2-11) and 0% in patients who received modified-dose anticoagulation. In conclusion, modified-dose anticoagulation appears to be a safe alternative to therapeutic anticoagulation in patients with cancer who develop deep vein thrombosis in the setting of thrombocytopenia.

Platelets and cancer-associated thrombosis.

Platelets have a newly appreciated and important role in many cancer-related processes, including tumor growth and metastases, angiogenesis, and promotion of a hypercoagulable state. Cancer patients commonly experience venous thromboembolism (VTE), a leading cause of mortality and a source of considerable morbidity and cost. The role of platelets in arterial thrombosis is well established, but emerging evidence supports the concept that platelets are also involved in initiation of VTE. This is particularly true in cancer-associated thrombosis as extensive new evidence shows that thrombocytosis and platelet activation are predictive biomarkers of VTE. The role of therapeutic anti-platelet agents has been proven effective at preventing VTE in non-cancer patients, and there are early data suggesting benefit in cancer patients as well. This review summarizes platelet-related predictive biomarkers of cancer-associated thrombosis, platelet-mediated mechanisms for VTE promotion in cancer patients, and anti-platelet agents in prevention of VTE.

Cancer-associated thrombosis.

Cancer-associated thrombosis accounts for almost one-fifth of all cases of venous thromboembolism (VTE) and is a leading cause of death, morbidity, delays in care, and increased costs. Our understanding of risk factors for cancer-associated thrombosis has expanded in recent years, and investigators have begun to use biomarkers and clinical prediction models to identify those cancer patients at greatest risk for VTE. The Khorana Risk Model, which is based on easily obtained biomarkers and clinical factors, has now been validated in several studies. Recent clinical trials of prophylaxis and treatment of VTE in cancer patients are reviewed here. In addition, consensus guidelines and expert opinion regarding management of VTE in specific challenging situations are presented.

Prevalence and clinical significance of incidental and clinically suspected venous thromboembolism in lung cancer patients.

BACKGROUND: It is unclear what proportion of VTE events in lung cancer patients are incidentally discovered and whether incidental events affect mortality. PATIENTS AND METHODS: We conducted a retrospective cohort study of lung cancer patients seen at the University of Rochester between January 1, 2006 and December 31, 2008 with the goal of quantifying and characterizing VTE events. Multiple clinical variables and mortality outcomes were compared using Kaplan-Meier survival analysis and multivariate Cox proportional hazards. RESULTS: The study population consisted of 207 subjects with lung cancer. The median age was 66 years and 55% were female (n = 115). Thirty-one patients (14.9%) experienced at least 1 VTE event with 32.2% (10/31) of these incidentally discovered. Incidental events comprised 29.4% (n = 5) of pulmonary embolisms, 11.1% (n = 2) of deep vein thrombosis, and 100% (n = 3) of visceral events. The median survival for patients with incidental VTE was 23.4 months (95% confidence interval [CI], 4.8-32.1) compared with 45.8 months (95% CI, 34.1-56.8) in patients without VTE (HR 2.4; 95% CI, 1.2-4.9; P = .01), but in a subgroup analysis of stage IV patients overall survival was not significantly different (HR, 0.94; P = .33). Patients with clinically suspected VTE had the lowest median survival at 13.1 months (95% CI, 6.4-18.9) which was significantly lower than patients without VTE (HR, 2.7; 95% CI, 1.6-4.5; P = .002), but not significantly different from patients with incidental VTE (HR, 1.2; 95% CI, 0.4-2.0; P = .7). In multivariate analysis, occurrence of VTE (HR, 2.3; 95% CI, 1.3-3.8; P = .002) was significantly associated with mortality when adjusting for age, stage, and histology. CONCLUSIONS: One-third of VTE events in lung cancer patients are incidentally discovered and VTE has negative clinical effect in lung cancer patients.

Health care costs associated with venous thromboembolism in selected high-risk ambulatory patients with solid tumors undergoing chemotherapy in the United States.

BACKGROUND: This study examines venous thromboembolism (VTE)-associated resource utilization and real-world costs in ambulatory patients initiating chemotherapy for selected common high-risk solid tumors. METHODS: Health care claims data (2004-2009) from the IMS/PharMetrics(®) Patient-Centric database were collected for propensity score-matched adult cancer (lung, colorectal, pancreatic, gastric, bladder, or ovarian) patients initiating chemotherapy with VTE (n = 912) and without VTE (n = 2736). Health care resource utilization (inpatient, outpatient, and outpatient prescription drug claims) and costs were compared between the two cohorts during the 12-month follow-up period after the index VTE event. Incremental costs were adjusted for demographic and clinical covariates. RESULTS: Cancer patients with VTE had approximately three times as many all-cause hospitalizations (mean 1.38 versus 0.55 per patient) and days in hospital (10.19 versus 3.37), and more outpatient claims (331 versus 206) than cancer patients without VTE (all P < 0.0001). Cancer patients with VTE incurred higher overall all-cause inpatient costs (mean USD 21,299 versus USD 7459 per patient), outpatient costs (USD 53,660 versus USD 34,232 per patient), and total health care costs (USD 74,959 versus USD 41,691 per patient) than cancer patients without VTE (all P < 0.0001). Total mean VTE-related health care costs were USD 9247 per patient over 12 months. Adjusted mean incremental all-cause health care costs of VTE were USD 30,538 per patient for cancer overall, ranging from USD 11,946 for gastric to USD 38,983 for pancreatic cancer. CONCLUSION: VTE is associated with significant inpatient and outpatient resource utilization, and increased all-cause (in addition to VTE-related) health care costs among ambulatory cancer patients. Measures to prevent outpatient cancer-associated VTE may reduce health care utilization and costs in this population.

Diabetes mellitus impacts risk of macrovascular invasion in patients undergoing transplantation for hepatocellular carcinoma.

BACKGROUND: Diabetes mellitus (DM) is identified as a negative prognostic indicator in hepatocellular carcinoma (HCC), though the basis for this is unknown. METHODS: This is a retrospective analysis of a prospectively collected database of 191 HCC patients treated at the University of Rochester Medical Center (URMC) with orthotopic liver transplantation between 1998-2008. Clinical characteristics were compared between patients with and without DM prior to liver transplantation and logistic regression analyses were conducted to assess the effect of DM on clinical outcomes including vascular invasion. RESULTS: Eighty-four of 191 (44%) transplanted patients had DM at time of transplantation. An association of DM with invasive disease was found among transplanted HCC patients where histologically confirmed macrovascular invasion was found in 20.2% (17/84) of diabetics compared to 9.3% of non-diabetics (10/107) (p=0.032). This difference also remained significant when adjusting for tumor size, number of nodules, age, obesity and etiologic risk factors in multivariate logistic regression analysis (OR=3.2, p=0.025). CONCLUSIONS: DM is associated with macrovascular invasion among a cohort of transplanted HCC patients.

Incidence and predictors of venous thromboembolism (VTE) among ambulatory high-risk cancer patients undergoing chemotherapy in the United States.

BACKGROUND: Recent studies suggest that thromboprophylaxis is beneficial in preventing venous thromboembolism (VTE) in cancer outpatients, but this is not widely adopted because of incomplete understanding of the contemporary incidence of VTE and concerns about bleeding. Therefore, the authors examined the incidence and predictors of VTE in ambulatory patients with bladder, colorectal, lung, ovary, pancreas, or gastric cancers. METHODS: Data were extracted from a large health care claims database of commercially insured patients in the United States between 2004 and 2009. Demographic and clinical characteristics of the cancer cohort (N = 17,284) and an age/sex-matched, noncancer control cohort were evaluated. VTE incidence was recorded during a 3-month to 12-month follow-up period after the initiation of chemotherapy. Multivariate analyses were conducted to identify independent predictors of VTE and bleeding. RESULTS: The mean age of the study population was 64 years, and 51% of patients were women. VTE occurred in 12.6% of the cancer cohort (n = 2170) over 12 months after the initiation of chemotherapy versus 1.4% of controls (n = 237; P < .0001); incidence ranged by cancer type from 19.2% (pancreatic cancer) to 8.2% (bladder cancer). Predictors of VTE included type of cancer, comorbidities (Charlson Comorbidity Index score or obesity), and commonly used specific antineoplastic or supportive care agents (cisplatin, bevacizumab, and erythropoietin). CONCLUSIONS: This large, contemporary, real-world analysis confirmed high rates of VTE in select patients with solid tumors and suggested that the incidence of VTE is high in the real-world setting. Awareness of the benefits of targeted thromboprophylaxis may result in a clinically significant reduction in the burden of VTE in this population.

Diabetes mellitus is associated with the presence of metastatic spread at disease presentation in hepatocellular carcinoma.

PURPOSE: Diabetes mellitus (DM) is identified as a negative prognostic indicator in hepatocellular carcinoma (HCC). METHODS: A retrospective review of HCC patients was conducted to assess the effect of DM on clinical variables. RESULTS: Ninety-seven of 265 (34%) patients had DM at the time of diagnosis. Distant metastasis was found in 33% (30/91) of patients with DM compared with only 9.7% (17/174) of those without DM (OR: 4.5, 95% CI: 2.3-8.8, p < .0001). This difference remained significant when adjusting for other clinical variables (OR: 10.0, 95% CI: 3.9-25.7, p < .0001). CONCLUSIONS: DM is associated with the presence of metastatic disease among a single institution cohort of HCC patients.

Leukocytosis, thrombosis and early mortality in cancer patients initiating chemotherapy.

BACKGROUND: Leukocytosis has been associated with thrombosis and mortality in cancer patients. We explored the association of leukocytosis with venous thromboembolism (VTE) and early mortality in cancer patients initiating chemotherapy. METHODS: Data from a prospective, multicenter observational study of treatment-related complications in 4,405 ambulatory cancer patients initiating chemotherapy was used for this analysis. The association of leukocytosis, VTE and mortality during the course of chemotherapy was evaluated in univariate and multivariate analysis. RESULTS: Ninety-three patients (2.1%) developed VTE and 134 (3%) died over a median follow up of 75 days (range 0-384). Of 4391 patients with available baseline white blood cell (WBC) count, 561 (12.8%) had elevated pretreatment leukocyte counts, defined as WBC > 11 x 10(9) cells/L. VTE occurred in 25 of 561 patients (4.5%) with baseline leukocytosis compared to 68 of 3830 (1.8%) with WBC

Emerging risk stratification approaches to cancer-associated thrombosis: risk factors, biomarkers and a risk score.

Cancer patients are well-known to be at increased risk of venous thromboembolism (VTE). However, the risk varies widely between patients and over the natural history of malignancy. Recent data have identified multiple clinical risk factors as well as biomarkers predictive of VTE. Risk factors include patient-associated factors such as age, obesity and medical comorbidities, cancer-associated factors such as site and stage of cancer, and treatment-associated factors, particularly chemotherapy and anti-angiogenic therapy. Biomarkers associated with increased risk of cancer-associated VTE include leukocyte count, platelet count, and levels of tissue factor, P-selectin and D-dimer. This review focuses on the evidence for risk stratification of cancer patients, based on these risk factors and biomarkers, as well as a recently validated predictive model which can be used to identify patients at highest risk. Targeted thromboprophylaxis utilizing model-based and/or biomarker-based approaches may provide an optimal risk-benefit ratio and is currently the focus of ongoing clinical trials.

Assessing risk of venous thromboembolism in the patient with cancer.

PURPOSE: Patients with cancer are increasingly at risk for venous thromboembolism (VTE). Rates of VTE, however, vary markedly among patients with cancer. DESIGN: This review focuses on recent data derived from population-based, hospital-based, and outpatient cohort studies of patients with cancer that have identified multiple clinical risk factors as well as candidate laboratory biomarkers predictive of VTE. RESULTS: Clinical risk factors for cancer-associated VTE include primary tumor site, stage, initial period after diagnosis, presence and number of comorbidities, and treatment modalities including systemic chemotherapy, antiangiogenic therapy, and hospitalization. Candidate predictive biomarkers include elevated platelet or leukocyte counts, tissue factor, soluble P-selectin, and D-dimer. A recently validated risk model, incorporating some of these factors, can help differentiate patients at high or low risk for developing VTE while receiving chemotherapy. CONCLUSION: Identifying patients with cancer who are most at risk for VTE is essential to better target thromboprophylaxis, with the eventual goal of reducing the burden as well as the consequences of VTE for patients with cancer.

Risk stratification for cancer-associated venous thromboembolism.

The risk of venous thromboembolism (VTE) is elevated in cancer, and thrombosis is the second leading cause of death in patients with malignancy. Many risk factors for cancer-associated thrombosis have been identified. These include patient-associated factors such as age, obesity and medical comorbidities; cancer-associated factors such as site and stage of cancer; and treatment-associated factors, particularly chemotherapy and hospitalization. In addition, several candidate biomarkers for cancer-associated thrombosis have been identified recently. Despite the high rate and significant impact of VTE in cancer outpatients, prior attempts at thromboprophylaxis in this population have not consistently demonstrated a benefit. This chapter will focus on risk stratification approaches, including a recently developed predictive model which can be used to identify those patients at highest risk. This model-based approach may have a significant impact on cancer-related morbidity, mortality and cost of care by directing targeted thromboprophylaxis in the future.

Incidence, risk factors and consequences of portal vein and systemic thromboses in hepatocellular carcinoma.

INTRODUCTION: Hemostatic activation may be important for tumor biology. Hepatocellular carcinoma (HCC) is commonly associated with portal vein thrombosis (PVT). Little is known about factors predictive for PVT in patients with HCC or its correlation with systemic venous thromboembolism (VTE). METHODS: We conducted a retrospective chart review of 194 consecutive patients diagnosed with HCC at the University of Rochester between 1998 and 2004 to identify the frequency and risk factors for PVT and its correlation with VTE and survival. RESULTS: Sixty patients (31%) had PVT with a higher rate in the non-transplant group compared to transplanted patients (34% vs. 24%; p=0.15). In multivariate analysis, Child Turcotte Pugh (CTP) class, stage, major vessel involvement, serum albumin, and serum AFP were independently associated with PVT (p<0.05 for each). The presence of PVT was associated with reduced survival (median survival 2.3 months for those with PVT versus 17.6 months for those without PVT, HR 2.05, p=0.004). The incidence of systemic VTE in the total population was 6.7%, and patients with PVT had a higher rate of systemic VTE compared to patients without PVT (11.5% vs. 4.4%; p=0.04). CONCLUSION: PVT is common in patients with HCC, indicates advanced disease, is associated with worse survival and correlates with systemic VTE, suggesting a common mechanism of hemostatic activation. Advanced stage, higher CTP class, major vessel involvement, low serum albumin, and high AFP levels are predictive of PVT in patients with HCC.

Inhibition of Mrp2- and Ycf1p-mediated transport by reducing agents: evidence for GSH transport on rat Mrp2.

Mammalian Mrp2 and its yeast orthologue, Ycf1p, mediate the ATP-dependent cellular export of a variety of organic anions. Ycf1p also appears to transport the endogenous tripeptide glutathione (GSH), whereas no ATP-dependent GSH transport has been detected in Mrp2-containing mammalian plasma membrane vesicles. Because GSH uptake measurements in isolated membrane vesicles are normally carried out in the presence of 5-10 mM dithiothreitol (DTT) to maintain the tripeptide in the reduced form, the present study examined the effects of DTT and other sulfhydryl-reducing agents on Ycf1p- and Mrp2-mediated transport activity. Uptake of S-dinitrophenyl glutathione (DNP-SG), a prototypic substrate of both proteins, was measured in Ycf1p-containing Saccharomyces cerevisiae vacuolar membrane vesicles and in Mrp2-containing rat liver canalicular plasma membrane vesicles. Uptake was inhibited in both vesicle systems in a concentration-dependent manner by DTT, dithioerythritol, and beta-mercaptoethanol, with concentrations of 10 mM inhibiting by approximately 40%. DTT's inhibition of DNP-SG transport was noncompetitive. In contrast, ATP-dependent transport of [(3)H]taurocholate, a substrate for yeast Bat1p and mammalian Bsep bile acid transporters, was not significantly affected by DTT. DTT also inhibited the ATP-dependent uptake of GSH by Ycf1p. As the DTT concentration in incubation solutions containing rat liver canalicular plasma membrane vesicles was gradually decreased, ATP-dependent GSH transport was now detected. These results demonstrate that Ycf1p and Mrp2 are inhibited by concentrations of reducing agents that are normally employed in studies of GSH transport. When this inhibition was partially relieved, ATP-dependent GSH transport was detected in rat liver canalicular plasma membranes, indicating that both Mrp2 and Ycf1p are able to transport GSH by an ATP-dependent mechanism.