Venous thromboembolism and occult malignancy

Trousseau is considered to be the first to have recognised a relation between venous thromboembolism (VTE) and malignancy. Illtyd James and Matheson in 1935 were the first in the Anglo-Saxon literature, at least to our knowledge, to report the observation of a patient with occult cancer at time of his venous thrombosis. Meanwhile, cancer has become an established risk factor for VTE. The prevalence of concomitant cancer in patients presenting with VTE varies considerably between the studies due to differences in, for instance, threshold of suspicion, screening methods, and characteristics of the patients like age. A consistent observation is the low prevalence of concomitant cancer in patients with secondary thrombosis, comparable to the prevalence in the general population. A 3–19-fold increase in prevalence of concomitant cancer has been reported in patients presenting with an idiopathic VTE. The same applies for occult cancer in patients with secondary and idiopathic VTE. The prevalence of occult cancer in patients with secondary VTE is comparable with the prevalence of cancer in the general population, while the prevalence of occult cancer in patients with idiopathic VTE is 4–10%. It seems possible to detect a substantial number of additional cancer patients, at time of diagnosis of idiopathic VTE, by means of extensive screening. However, results of randomised trials, evaluating the effect on survival rate, are lacking.     

Epidemiology and management of venous thromboembolism in patients with cancer

Cancer and its treatments are well-recognized risk factors for venous thromboembolism (VTE). Although the incidence of VTE in cancer patients is not well documented, there is evidence that the absolute risk depends on the tumor type, the stage or extent of the cancer, and treatment with antineoplastic agents. The most common cancer types seen in patients with thrombosis are breast, colorectal and lung, reflecting the prevalence of these malignancies in the general population. When the underlying prevalence is taken into account, cancers of the pancreas, ovary and brain are the most strongly associated with thrombotic complications. Although idiopathic thrombosis can be the first manifestation of an occult malignancy, extensive screening for cancer in these patients has not been shown to improve survival and is not warranted. Prophylaxis in patients undergoing major surgery for cancer with either unfractionated or low-molecular-weight heparin (LMWH) is strongly recommended, but prophylaxis in ambulatory medical oncology patients is not routinely indicated. Anticoagulant therapy remains the mainstay treatment of VTE in cancer patients and recent evidence shows that LMWH is effective and well tolerated for both initial therapy and secondary prophylaxis. Despite treatment, cancer patients with thrombosis have a poor prognosis. This is likely due to premature deaths from recurrent VTE and to the aggressive nature of the underlying cancer. Whether LMWH is capable of modifying tumour biology remains unanswered. Further research is needed to address the many clinical questions in the management of thrombosis in patients with cancer.     

Low molecular weight heparins in cancer. Management and prevention of venous thromboembolism in patients with malignancies

Management and prevention of venous thromboembolism (VTE) in cancer patients is challenging. Not only is the risk of VTE in cancer patients elevated compared to patients without malignancies, but also is standard treatment based on Vitamin K antagonists (VKAs) less effective and associated with an increased frequency of major bleeding. Therapy with Low Molecular Weight Heparin (LMWH) is less sensitive to drug interactions, not hindered by a narrow therapeutic window and needs no monitoring. LMWH therapy therefore seems more practical and may also be more effective in cancer patients. Moreover a possible survival benefit has been suggested, the underlying mechanism of which is not yet unraveled. A combination of cancer and thrombosis is a predictor of poor long-term survival. Anticoagulant drugs, especially LMWH, may be of influence on tumor progression. Hypercoagulability in cancer patients may indicate an aggressive change in the tumor and is associated with tumor progression. Hypercoagulability could on the other hand also be a risk factor for developing cancer. To assist clinicians in defining the role of LMWH in cancer patients, we categorized, summarized and critically weighed all available evidence on the subject. Based on available data derived from clinical trials recommendations on the application of heparin in oncological patients are made. However, many uncertainties remain regarding the subject of cancer related thrombosis in view of treatment and the possible effects on tumor biology by heparins.     

Cancer, thrombosis and heparin-induced thrombocytopenia

Venous thromboembolism (VTE) is a common occurrence in patients with cancer, and can sometimes precede the development of the clinical manifestations of cancer. The pathogenetic mechanisms of thrombosis involve a complex interaction between tumour cells and the host haemostatic system, in addition to cancer-related clinical risk factors. The risk of VTE increases in presence of distant metastases. The development of VTE in patients with cancer is a strong predictor of decreased survival. The most common medical situations that make cancer patients at a higher risk of VTE include immobilization and chemotherapy with or without adjuvant hormone therapy. Recent findings suggest that heparin-induced thrombocytopenia (HIT) and HIT-related thrombotic complications may occur in cancer patients with a higher frequency than in patients free from malignancy. Thromboembolism is a well-recognised complication of malignant disease. Clinical manifestations vary from venous thromboembolism (VTE) to disseminated intravascular coagulation, more commonly observed in patients with haematological malignancies and those with widespread metastatic cancer, to arterial embolism, more commonly observed in patients undergoing chemotherapy and in those with non-bacterial thrombotic endocarditis.     

Mutations in NSCLC and their link with lung cancer-associated thrombosis: A case-control study

Introduction

The association of venous thromboembolic events (VTE) and lung cancer is highly prevalent. Additionally, the occurrence of a VTE with cancer has been associated with a worse prognosis and a poor quality of life. Underlying cancer biological features such as tumour mutations may contribute to VTE risk and cancer prognosis. Since preclinical data suggest a link between thrombosis and KRAS mutations in tumours, we aimed to validate this association in a patient registry cohort. Methods: A retrospective case control study was performed using the CHUM NSCLC registry. Cases had VTE occurring 6 months previous to or after a diagnosis of NSCLC. Diagnosis of VTE (venous thrombosis, pulmonary embolism, and migratory superficial thrombophlebitis) was confirmed by a review of the imaging reports. Controls were patients with NSCLC without thrombosis matched for age and stage (I-IIIA/IIIB-IV). Exclusion criteria included insufficient tissue for KRAS/EGFR mutation analysis or insufficient clinical information.

Results

Between Jan 2000 and Dec 2009 a total of 57 cases with VTE and 102 controls without VTE were included. The OR for thrombosis in KRAS and EGFR mutated NSCLC patients are respectively 2.67 (1.12-6.42; p = 0.014) and 0.99 (0.27-3.48; p = 0.99).

Conclusions

KRAS mutation is associated with an increased risk of VTE in this NSCLC cohort. These findings are consistent with preclinical studies. Prospective data on VTE rates from clinical trials with molecularly defined NSCLC are needed to confirm these findings.     

Prevalence of factor V Leiden,FII G20210A,FXIII Val34Leu and MTHFR C677T polymorphisms in cancer patients with and without venous thrombosis

Venous thromboembolism (VTE) is a common complication in patients with malignant disease. In addition to well-established acquired risk factors for VTE, several genetic risk factors, mainly related to the haemostatic system, are known to influence thrombotic risk. However, the contribution of gene abnormalities to thrombotic tendency in cancer patients remains poorly explored. We performed a prospective study to evaluate the prevalence and clinical significance of four gene variations (factor V Leiden [FVL], factor II G20210A, factor XIII Val34Leu and MTHFR C677T) in cancer patients, with and without VTE. Enrolled were 211 unrelated and unselected patients (M/F ratio 0.5, mean age 57 years, range 12-91 years) with a diagnosis of cancer, admitted to two University Oncology Clinics in the city of S?o Paulo, Southeastern Brazil. After admission, all patients were evaluated for the presence of symptoms and signs of VTE. Sixty-four patients (30.3%) had an episode of deep venous thrombosis (DVT) or pulmonary embolism (PE), which has been objectively verified; 147 patients (69.7%) had no evidence of VTE. FVL was found with a frequency of 1.5% and 2.7% in the VTE and non-VTE group, respectively (odds ratio [OR] for VTE 0.6, 95% CI: 0.06-5.3). FII G20210A was found in 1.5% and 1.3% of thrombotic and nonthrombotic patients, respectively, yielding an OR of 1.2 (95% CI: 0.1-13.1). FXIII Val34Leu was detected in 29.6% of the thrombotic patients and in 28.5% of the non-thrombotic patients (OR 1.1, 95% CI: 0.5-2). MTHFR 677T was present in 53.1% and 60.5% of patients with and without thrombosis, respectively (OR 0.8, 95% CI: 0.4-1.4). The present data do not point to an association between the four polymorphisms here investigated and the risk of VTE in cancer patients.     

Venous thromboembolism in patients with pancreatic adenocarcinoma: lower incidence in Asian ethnicity

BACKGROUND: Pancreatic adenocarcinoma is one of the cancers most frequently associated with venous thromboembolism (VTE), with the varying incidences of 10%-20% reported in Western countries. Asians are known to have a lower risk for VTE than Caucasians, but few studies have been conducted regarding the incidence of VTE in Asian cancer patients. MATERIALS AND METHODS: Incidence of radiologically confirmed VTE was assessed by review of medical records of all patients histologically diagnosed with advanced pancreatic adenocarcinoma, with follow-up conducted at a regional teaching hospital from Jun 2003 to Dec 2005. RESULTS: Seventy five patients with advanced pancreatic adenocarcinoma were identified for evaluation (M:F=44:31, locally advanced:metastatic=25:50, median age:67 years). Four patients (5.3%) developed VTE during median follow-up period of 124 days. Three of four patients had metastatic disease and were receiving chemotherapy when VTE developed. The mean time from cancer diagnosis to the detection of VTE was 160 days. No episodes of peripheral arterial thrombosis were detected, but three multiple cerebral infarctions occurred, which proved fatal in all three. Median survival time was shorter in patients with VTE than those without, but the difference was not statistically significant (4.3 vs 6.6 months). CONCLUSION: The incidence of VTE complications in Korean patients with advanced pancreatic cancer was 5.3%, which is lower than that observed in other ethnic groups. Our study warrants further prospective investigations on the incidence and mechanism of VTE and cerebral infarctions in cancer patients of different ethnic groups.     

Accounting for death as a competing risk in cancer-associated thrombosis studies

In recent years, clinical investigation in the field of cancer-associated thrombosis has identified a number of potential biomarkers to predict the risk of developing a thrombotic event. Similarly, large randomized clinical trials have demonstrated the benefit of low molecular weight heparins in the treatment as well as prevention of venous thromboembolic events (VTE) in cancer patients. However, the most common statistical methodology to evaluate the occurrence of VTE has been the Kaplan-Meier approach. When used to estimate the cumulative incidence of VTE in cancer studies, the Kaplan-Meier method over-estimates the cumulative incidence function due to failure to account for death as a competing risk for the development of VTE. A more appropriate statistical estimate of cumulative incidence of VTE in cancer studies is the competing risk model. This review describes the theoretical and mathematical basis for estimating the cumulative incidence function by the competing risk model for the analysis of VTE outcomes in cancer-associated thrombosis.     

Thromboprophylaxis in non-surgical cancer patients

Acutely ill medical patients with cancer and cancer patients requiring non-surgical therapy are considered as non-surgical cancer patients and are at moderate to high risk of venous thromboembolism (VTE): approximately 10-30% of these patients may develop asymptomatic or symptomatic deep-vein thrombosis (DVT) or pulmonary embolism (PE), and the latter is a leading contributor to deaths in hospital. Other medical conditions associated with a high risk of VTE include cardiac disease, respiratory disease, inflammatory bowel disease, rheumatological and infectious diseases. Pre-disposing risk factors in non-surgical cancer patients include a history of VTE, immobilisation, history of metastatic malignancy, complicating infections, increasing age, obesity hormonal or antiangiogenic therapies, thalidomide and lenalidomide therapy. Heparins, both unfractionated (UFH) and low molecular weight heparin (LMWH) and fondaparinux have been shown to be effective agents in prevention of VTE in the medical setting with patients having a history of cancer. UFH and LMWH along with semuloparin also have a role in outpatients with cancer receiving chemotherapy. However, it has not yet been possible to demonstrate a significant effect on mortality rates in this population. UFH has a higher rate of bleeding complications than LMWH. Thromboprophylaxis has been shown to be effective in medical patients with cancer and may have an effect on cancer outcomes. Thromboprophylaxis in patients receiving chemotherapy remains controversial and requires further investigation. There is no evidence for the use of aspirin, warfarin or mechanical methods. We recommend either LMWH, or fondaparinux for the prevention of VTE in cancer patients with acute medical illnesses and UFH for those with significant severe renal impairment. For ambulatory cancer patients undergoing chemotherapy we recommend LMWH or semuloparin. These are safe and effective agents in the thromboprophylaxis of non-surgical cancer patients.     

High prevalence of recurrent thrombosis in subsets of cancer patients with isolated gonadal vein thrombosis: A single center retrospective study

Purpose

Cancer patients are a high-risk population for venous thromboembolism (VTE); the natural history of gonadal vein thrombosis (GVT) occurring in cancer patients is not well described in the medical literature.

Methods

Utilizing a software program the computerized tomographic scan reports of patients at a single cancer center from January 1, 2004 to June 30, 2011 were searched for the term GVT. Patients included in this analysis had a diagnosis of cancer, an isolated GVT (i.e. no evidence of thrombosis at another site), no symptoms referable to the GVT, and at least six months of follow-up information. All subsequent recurrent VTE events were confirmed by imaging studies.

Results

196 cancer patients with GVT were identified. The majority of patients in this analysis had metastatic disease (118, 61.2%) as well as active cancer (167, 85.2%). Twenty patients (10.8%) developed recurrent VTE (median follow-up 14.5 months); median time to recurrent VTEs was 5.5 months (range 0–19 months). When considering only patients with without a recent history of gynecologic surgery, VTE recurrence rates were 14.3%. Active cancer was the only risk factor significantly associated with recurrent VTE (P = 0.047).

Conclusions

Based upon the patient’s risk factors for VTE, treatment of an incidentally detected GVT in cancer patients with anticoagulation, as per guidelines for other VTE sites, may be indicated in certain high risk subgroups, especially those patients with active cancer who have not had prior pelvic surgery.     

Long-term death and recurrence in patients with acute venous thromboembolism: The MASTER registry

BACKGROUND: The long-term clinical outcome of VTE has been essentially assessed in cohorts of selected patients. The aim of this multicenter registry was to prospectively assess the long-term clinical outcome in a cohort of unselected patients with objectively confirmed acute VTE. MATERIALS AND METHODS: Death and VTE recurrence at 24months were the main study outcomes. Univariate and multivariate survival analyses were performed according to the Kaplan-Meyer and Cox proportional hazard model, respectively. RESULTS: 2119 patients with acute VTE were included in the registry: 1541 (72.7%) with deep vein thrombosis, 206 (9.7%) with pulmonary embolism and 372 (17.6%) with both. Information about death was available in 2021 patients (95.4%) and about recurrence in 1988 patients (93.8%). 167 patients (4.55% patient-year) died during follow-up. After adjusting for age, cancer (Hazard ratio [HR]: 7.2; 95%CI 4.8-10.8), long-term heparin treatment (HR: 2.5; 95%CI 1.8-3.5), in-hospital management of VTE (HR: 2.0; 95%CI 1.3-3.0), and ileo-caval thrombosis (HR: 1.7; 95%CI 1.2-2.4) were found to be independent predictors of death. 124 (3.63% patient-year) patients had a VTE recurrence during follow-up. In-hospital management of VTE (HR: 1.8; 95%CI 1.2-2.9), male gender (HR: 1.7; 95%CI 1.2-2.4) were independent risk factors for recurrent VTE. Cancer (HR: 1.6; 95%CI 1.0-2.8) showed a trend for increased risk of VTE recurrence (p=0.056). The reported rate of major bleeding was 2.5%. CONCLUSIONS: In a large cohort of unselected VTE patients, cancer, ileo-caval thrombosis, long-term heparin treatment and in-hospital management were associated with increased mortality during long-term follow-up. In-hospital management, male gender were associated with an increased risk of VTE recurrence.     

Incidental venous thromboembolism in cancer patients: prevalence and consequence

Introduction

Careful re-evaluation of CT-scans for cancer staging frequently reveals unsuspected venous thromboembolism (VTE) on CT-scans. However, it is unknown how often these findings lead to anticoagulant treatment in daily clinical practice.

Methods

Reports from thoracic and/or abdominal CT-scans performed in a consecutive series of patients to stage cancer were retrospectively evaluated to determine the prevalence of incidental venous thromboembolism (iVTE). Presence of pre-existing signs of VTE, anticoagulant treatment and 3-month follow-up were analysed in patients with iVTE.

Results

A total of 1466 staging scans (838 patients) from the year 2006 were included in the analysis. The prevalence of VTE in patients was 2.5% (21/838 patients, 95% confidence interval 1.6-3.8%); the prevalence of VTE on scans was 1.4% (21/1466 scans, 95% CI 0.9-2.2%). Incidental PE or deep vein thrombosis (DVT) was observed in 11 (1.3%, 0.7-2.3%) and abdominal vein thrombosis in 9 patients (1.1%, 0.6-2.0%; in the portal (5), mesenteric (3) and renal vein (1), respectively). Nine out of eleven patients with PE/DVT were treated with anticoagulants, while none of the patients with thrombosis in other locations received anticoagulants. One of these patients developed symptomatic PE one month later; otherwise, follow up was uneventful in the untreated patients.

Conclusion

The prevalence of iVTE in patients with cancer in clinical practice is relatively low and most patients with PE or DVT are treated with anticoagulants. For patients with thrombi in other locations, further research is necessary to understand the natural history of these thrombi in order to develop adequate guidelines.     

Dose escalation of low molecular weight heparin in patients with recurrent cancer-associated thrombosis

Introduction

Patients with cancer-associated thrombosis are at a high risk of developing recurrent events despite anticoagulant therapy. Escalation of the dose of low molecular weight heparin (LMWH) has been suggested as a potential treatment option to manage these patients. We sought to confirm the benefit and risk of this management strategy in patients with recurrent cancer-associated thrombosis.

Material and Methods

A retrospective cohort study of consecutive cancer outpatients seen for management of a symptomatic recurrent cancer-associated thrombosis while on anticoagulation was undertaken. Objectively confirmed episodes of recurrent thrombosis were treated with either dose escalation of LMWH or initiation of therapeutic dose of LMWH in patients already anticoagulated with LMWH or vitamin K antagonist (VKA) respectively. Included patients were followed for a minimum of 3 months after the index recurrent event.

Results

Fifty-five cancer patients with a recurrent venous thromboembolism (VTE) despite anticoagulation were included. At the time of the recurrence, 89% of patients were on LMWH. The median time between the initial cancer-associated thrombosis to the index recurrent event was 2.3 months (range 0.1 to 30.4 months). Four patients (7.3%; 95% CI: 2.0 to 17.6%) had a second recurrent VTE during the 3-month follow-up period. Three patients (5.5%; 95% CI 1.1 to 15.1%) had major bleeding complications after dose escalation of LMWH. There were no recurrent fatal VTE or major bleeding episodes.

Conclusion

Escalating the dose of LMWH seems effective and safe for managing patients with recurrent cancer-associated thrombosis despite anticoagulant therapy.     

The MASTER registry on venous thromboembolism: description of the study cohort

INTRODUCTION: Information on the epidemiology and long-term clinical outcome of venous thromboembolism (VTE) is mainly based on data from clinical trials and thus may be not representative of the full spectrum of VTE patients. The aim of this multicenter registry (MASTER) was to prospectively collect data on the epidemiology and long-term clinical outcome of VTE in an unselected cohort of patients. MATERIALS AND METHODS: In symptomatic patients with objectively confirmed acute VTE, information about clinical presentation, diagnostic methods, temporary and permanent risk factors, pre-event prophylaxis and treatment were captured by an electronic data network at the time of the index event. A 24-month follow-up is currently ongoing. RESULTS: From January 2002 to October 2004, 2119 patients were included in the MASTER registry in 25 Italian centers. At entry, the mean patient age was 59.3+/-18.1 years (range 18-99 years). 1541 patients (72.7%) were affected by deep vein thrombosis, 206 patients (9.7%) by pulmonary embolism and 372 patients (17.5%) by both deep vein thrombosis and pulmonary embolism. 676 patients (31.9%) received home-treatment. 899 patients (42.4%) had one or more temporary risk factors. 381 patients (18.0%) had a known cancer at the time of the index event and in 50 patients (2.4%) a new cancer was discovered at the time of the index event. 311 patients (14.7%) had a previous VTE. CONCLUSIONS: Following a real world approach, our registry describes the clinical presentation, risk factors, diagnosis and treatment procedures in a large cohort of unselected patients with VTE.     

Long-term anticoagulation treatment for acute venous thromboembolism in patients with and without cancer. The SWIss Venous ThromboEmbolism Registry (SWIVTER) II

In patients with acute cancer-associated thrombosis, current consensus guidelines recommend anticoagulation therapy for an indefinite duration or until the cancer is resolved. Among 1,247 patients with acute venous thromboembolism (VTE) enrolled in the prospective Swiss Venous Thromboembolism Registry (SWIVTER) II from 18 hospitals, 315 (25%) had cancer of whom 179 (57%) had metastatic disease, 159 (50%) ongoing or recent chemotherapy, 83 (26%) prior cancer surgery, and 63 (20%) recurrent VTE. Long-term anticoagulation treatment for >12 months was more often planned in patients with versus without cancer (47% vs. 19%; p<0.001), with recurrent cancer-associated versus first cancer-associated VTE (70% vs. 41%; p<0.001), and with metastatic versus non-metastatic cancer (59% vs. 31%; p<0.001). In patients with cancer, recurrent VTE (OR 3.46; 95%CI 1.83-6.53), metastatic disease (OR 3.04; 95%CI 1.86-4.97), and the absence of an acute infection (OR 3.55; 95%CI 1.65-7.65) were independently associated with the intention to maintain anticoagulation for >12 months. In conclusion, long-term anticoagulation treatment for more than 12 months was planned in less than half of the cancer patients with acute VTE. The low rates of long-term anticoagulation in cancer patients with a first episode of VTE and in patients with non-metastatic cancer require particular attention.     

Predictive potential of haemostatic biomarkers for venous thromboembolism in cancer patients

Venous thromboembolism (VTE) is a common problem in cancer patients. However, the rates of VTE vary widely between different types of malignancies. Furthermore, patient- and treatment-related risk factors contribute to the risk of VTE. The prediction of the individual risk of VTE and the identification of patients with cancer that might benefit from thromboprophylaxis is a major clinical challenge, because the pathogenesis of cancer-associated VTE is multifactorial. Therefore, recent studies have focused on identification of predictive biomarkers for VTE. As there is a close interrelation between cancer and the haemostatic system, which leads to activation of haemostasis and fibrinolysis, biomarkers of the haemostatic system seem to be promising in predicting risk of developing VTE in cancer patients. Some candidate biomarkers or laboratory tests of the haemostatic system including platelet count, soluble P-selectin, tissue factor (TF) and TF-bearing microparticles, coagulation factor VIII, D-dimer, prothrombin fragment 1+2 and the thrombin generation assay have been reported to predict cancer-associated VTE. In addition, it has been shown that risk-scoring models, incorporating clinical parameters and biomarkers, allow risk stratification of cancer patients into groups at high- and at low risk of VTE. The accuracy of a previously established risk scoring model can be improved when it is expanded and biomarkers of the haemostatic system are added. The benefit of a targeted thromboprophylaxis for primary prevention of VTE in cancer patients based on risk assessment by measuring biomarkers or applying risk scoring models has to be shown in interventional clinical trials.     

Predicting recurrences or major bleeding in women with cancer and venous thromboembolism. Findings from the RIETE Registry

BackgroundCancer patients with venous thromboembolism (VTE) have an increased incidence of recurrences and bleeding complications Reliable information on the factors determining the risk for such complications may facilitate better use of therapy.MethodsRIETE Registry is an ongoing, international registry of consecutive patients presenting with symptomatic acute VTE confirmed by objective tests. We assessed the 3-month outcome in all women with active cancer, trying to identify if differences exist according to the tumor site.ResultsUp to May 2007, 18,883 patients had been enrolled. Of them, 3805 (20%) had active cancer, 1719 (45%) were women. During the 3-month study period, 40 (2.3%) had recurrent deep vein thrombosis, 39 (2.3%) recurrent pulmonary embolism (PE), 67 (3.9%) major bleeding, 394 (23%) died. Of these, 13 (33%) women with recurrent PE died of the PE, 17 (42%) with major bleeding had fatal bleeding. In women with gastrointestinal (5.7% vs. 4.3%) or genitourinary (6.4% vs. 4.7%) cancers the incidence of bleeding complications exceeded that of VTE recurrences, while in those with brain (3.4% vs. 13%) or lung cancer (2.6% vs. 11%) the rate of recurrences outweighed that of major bleeding.ConclusionsWe identified significant differences in outcome according to the site of cancer that may help to identify those women with cancer and VTE at a higher risk for recurrences or major bleeding.     

The effects of low molecular weight heparins on venous thromboembolism and survival in patients with cancer

Monotherapy with low molecular weight heparin (LMWH) is superior to vitamin K antagonists in preventing recurrent venous thromboembolism (VTE) in patients with cancer and may improve the survival of patients with less advanced malignancies. These agents are also the preferred anticoagulants for primary prophylaxis in medical and surgical patients in hospital. Despite their limitations, LMWHs have improved the quality of care and quality of life in patients with VTE. Recent research has also explored the role of LMWH as anticancer agents. Evidence from experimental studies have demonstrated inhibitory effects of LMWH on various processes that are necessary for tumour growth and progression while results from clinical trials have shown a reduction in overall mortality in patients treated with LMWH. However, because of limitations and differences in study designs as well as small sample sizes, it remains uncertain whether the reduction in mortality is real and whether LMWH achieve this effect through inhibition of coagulation, non-anticoagulant mechanisms or both. Multiple anticancer mechanisms, including inhibition of tumour angiogenesis, interference with tumour cell adhesion, and suppression of tumour cell invasion, have been demonstrated in experimental models with LMWH, but none have been confirmed in vivo in humans. This review will briefly summarize the data on the treatment of VTE in cancer patients with LMWH and discuss the experimental and clinical data on its possible anticancer effects.     

Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry

Cancer patients with acute venous thromboembolism (VTE) have an increased incidence of recurrences and bleeding complications while on anticoagulant therapy. Methods RIETE is an ongoing registry of consecutive patients with acute VTE. We tried to identify which cancer patients are at a higher risk for recurrent pulmonary embolism (PE), deep vein thrombosis (DVT) or major bleeding. Up to May 2007, 3,805 cancer patients had been enrolled in RIETE. During the first three months of follow-up after the acute, index VTE event, 90 (2.4%) patients developed recurrent PE, 100 (2.6%) recurrent DVT, 156 (4.1%) had major bleeding. Forty patients (44%) died of the recurrent PE,46 (29%) of bleeding. On multivariate analysis, patients aged <65 years (odds ratio [OR]: 3.0; 95% confidence interval [CI]: 1.9-4.9), with PE at entry (OR: 1.9; 95% CI: 1.2-3.1), or with <3 months from cancer diagnosis to VTE (OR: 2.0; 95% CI: 1.2-3.2) had an increased incidence of recurrent PE. Those aged <65 years (OR: 1.6; 95% CI: 1.0-2.4) or with <3 months from cancer diagnosis (OR: 2.4; 95% CI: 1.5-3.6) had an increased incidence of recurrent DVT. Finally, patients with immobility (OR: 1.8; 95% CI: 1.2-2.7), metastases (OR: 1.6; 95% CI: 1.1-2.3), recent bleeding (OR: 2.4; 95% CI: 1.1-5.1), or with creatinine clearance <30 ml/min (OR: 2.2; 95% CI: 1.5-3.4), had an increased incidence of major bleeding. With some variables available at entry we may identify those cancer patients withVTE at a higher risk for recurrences or major bleeding.     

Increased risk of venous thromboembolism in patients with primary mediastinal large B-cell lymphoma

Background

Primary mediastinal large B-cell lymphoma (PMBCL) is a rare subtype of diffuse large B-cell lymphoma, arising in the mediastinum. Compression of large mediastinal vessels is common in patients with PMBCL, predisposing these patients to venous thrombosis. The incidence of this complication is still unknown.

Materials and methods

We conducted a retrospective chart review of 42 consecutive patients diagnosed with PMBCL at a Clinic for hematology, Clinical Center of Serbia between 1999 and 2009 to identify the frequency and risk factors for venous thromboembolic disease (VTE) and its correlation with survival.

Results

In the subgroup of patients with thrombosis (VTE subgroup) were 15/42 patients (35.7%): 14 patients had deep venous thrombosis and 1 had pulmonary embolism. Ten patients had a thrombosis at the moment of diagnosis PMBCL, while in five thrombosis occurred during the course of the disease. According to hemostasis variables, patients in the VTE subgroup had significantly higher fibrinogen (P = 0.02) and D-Dimer (P < 0.001). Also, patients in the VTE subgroup had significantly larger diameter of mediastinal tumor mass (P = 0.01) and the incidence of syndrome venae cava superior (P = 0.009). The median survival rate in the VTE subgroup was 45 months (95% CI; 22 to 68 months) while in the NVTE it was 93 (95% CI; 46 to 140 months), (log rank P = 0.058).

Conclusions

VTE is a common complication in PMBCL patients and according to our results negatively influences survival. Use of antithrombotic prophylaxis may be considered together with chemotherapy, especially in those with bulky mediastinal tumor mass.