Atorvastatin favorably modulates proinflammatory cytokine profile in patients following deep vein thrombosis

Background

Venous thromboembolism (VTE) has been shown to be associated with inflammation. Statins that might reduce VTE risk have been found to exert anti-inflammatory properties in patients at cardiovascular risk. We sought to investigate whether anti-inflammatory effects of atorvastatin can be observed in VTE patients.

Materials and Methods

Atorvastatin 40 mg/d was given for 3 days to 26 consecutive VTE patients following discontinuation of anticoagulant therapy and 25 controls. We evaluated interleukin (IL)-1b, IL-6, IL-8, IL-10, soluble P-selectin and von Willebrand factor (vWF) antigen in peripheral venous blood.

Results

The VTE patients displayed higher C-reactive protein (p = 0.013), IL-1b (p = 0.03), IL-8 (p = 0.03) and vWF (p < 0.0001) compared with the controls. In VTE patients atorvastatin decreased IL-6 (p = 0.0003), IL-8 (p = 0.003) and P-selectin (p < 0.0001), but increased IL-10 (p = 0.001), with no association with C-reactive protein or cholesterol-lowering effects. Atorvastatin reduced IL-1b (p = 0.01), IL-6 (p = 0.03) and P-selectin (p = 0.002) in controls. Residual venous thrombosis was associated with elevated IL-6 and P-selectin, whereas patients with proximal deep vein thrombosis showed elevated P-selecitn prior to and following statin administration (all p < 0.05).

Conclusion

A 3-day administration of atorvastatin reduces inflammation without decrease in C-reactive protein in VTE patients.     

Inhibitory effects of bortezomib on platelet aggregation in patients with multiple myeloma

Introduction

Multiple myeloma (MM) therapy affects prothrombotic and anticoagulant processes. Patients receiving thalidomide, especially in combination with steroids, are at increased risk of venous thromboembolism (VTE), while the incidence of VTE on bortezomib is low. In vitro studies indicate that bortezomib causes a reduction in ADP-induced platelet aggregation.

Objectives

To analyse the influence of bortezomib on platelet aggregation induced by various agonists in patients with MM.

Patients and Methods

A total of 30 patients (median age 57.5 years) with relapsed/refractory MM receiving bortezomib-based regimens were analysed. Optical platelet aggregometry was performed with the agonists collagen, ADP and ristocetin and measured over two 21-day cycles. The results from two groups: those treated with bortezomib and thalidomide (BT group, n = 11) and those without thalidomide (B group, n = 19) were analysed.

Results

During the second cycle, significantly decreased platelet aggregation was observed in the B group: 5 μM ADP (p = 0.0285, day 1 versus 8); 3.5 μM ADP (p = 0.0005, day 1 versus 8 and day 1 versus 11), collagen (p = 0.0014, day 4 versus 8, day 4 versus 11), 1.25 mg/ml ristocetin (p = 0.0017, day 1 versus 8 and day 1 versus 11). Agonist-induced platelet aggregation tended to be reduced over time during the 1st cycle in group B. In the thalidomide group, significant platelet aggregation inhibition by collagen only was found. Transient reduction in platelet count was observed in all patients, but more prominently in group B.

Conclusion

The inhibitory effects of prolonged exposure of bortezomib on platelet aggregation were demonstrated in relapsed/refractory MM patients, but antithrombotic activity of bortezomib should be clarified in further prospective studies.     

Statins are Associated with Low Risk of Venous Thromboembolism in Patients with Cancer: A Prospective and Observational Cohort Study

Introduction

Patients with cancer are at risk of venous thromboembolism (VTE). Statin-use has been shown to be associated with low risk of VTE in patients without cancer, but data in cancer patients is scarce. The objective of this study was to evaluate the association of statins with risk of VTE in cancer patients in a prospective observational cohort study.

Materials and Methods

Patients with newly diagnosed cancer or progression of disease after remission were included and prospectively followed for a maximum of 2 years. Study endpoint was occurrence of symptomatic VTE.

Results

Patients (n = 1434) were followed over a median observation period of 729 days. VTE occurred in 107 (7.5%) patients. At study inclusion, 170 (11.9%) patients took statins. Simvastatin (n = 96) and atorvastatin (n = 48) were the most frequently prescribed statins. VTE occurred in 6 (3.5%) patients with statins. Patients with statins had a lower risk of VTE than patients without (subhazard ratio 0.43, 95% confidence interval 0.19 to 0.98; p = 0.04). In competing risk analysis, the cumulative probability of VTE in patients with statins was 2.94% after 12 months and 3.54% after 24 months, compared to 7.13% and 8.13% in the group without statins (Gray’s test: p = 0.04).

Conclusion

This study provides observational evidence for an association between statin use and low risk of VTE in patients with cancer. The role of statins for prevention of cancer-associated VTE needs to be confirmed in randomized, controlled trials.     

The role of soluble P selectin in the diagnosis of venous thromboembolism

Introduction

Soluble P selectin (sPsel), a member of the selectin family of cell adhesion receptors, has been proposed as a key molecule in hemostasis and thrombosis mediating platelet rolling, generating procoagulant microparticles and enhancing fibrin deposition. The aim of this study was to examine the role of sPsel in the diagnosis of venous thromboembolism (VTE).

Materials and Methods

We performed a systematic review and we used meta-analysis to synthesize data from published studies reporting sPsel levels in patients with i) VTE (deep venous thrombosis; DVT or DVT and pulmonary embolism; PE) and ii) DVT only. Pooled Odds Ratios (ORs) with 95% Confidence Intervals (CIs) were appropriately calculated among patients and controls. Diagnostic performance of sPsel was tested with pooled sensitivity, specificity, Diagnostic Odds Ratio (DOR) and summary receiver operator characteristic (SROC) curve.

Results

Eleven studies, comprising of 586 VTE patients and 1,843 controls were deemed eligible. The sPsel was significantly increased after VTE (OR = 2.89, 95%CI = 2.31-3.61, p < 0.001), or DVT only (OR = 2.64, 95%CI = 1.95-3.56, p < 0.001). Subgroup analysis evidenced that sPsel was also increased after VTE when evaluating only studies with patients that had no prior medical history (OR = 2.88, 95%CI = 1.98-4.19, p < 0.001). Exclusion of studies including patients with solid organ tumor, HIV or lupus anticoagulants positive patients did not alter findings. Pooled sensitivity and specificity of sPsel was 0.57 (95%CI = 0.30-082, p < 0.001) and 0.73 (95%CI = 0.51-0.90, p < 0.001), respectively and DOR was 4.31 (95%CI = 2.22-8.37, p < 0.01). SROC curve yielded in significant accuracy of sPsel performance (AUC = 0.74, p = 0.05).

Conclusions

The sPsel was significantly elevated in patients with DVT, both uncomplicated and complicated with PE and presented with high levels of diagnostic performance. sPsel is a plasma biomarker that may help in the diagnosis of VTE.     

Risk-assessment and pharmacological prophylaxis of venous thromboembolism in hospitalized patients with chronic liver disease

Introduction

There is a lack of evidence regarding the need for thromboprophylaxis in hospitalized patients with liver disease. The purpose of this study was to evaluate the Padua Predictor Score (PPS) as a risk-stratification tool for the development of venous thromboembolism (VTE) in patients with chronic liver disease.

Methods

This was a retrospective cohort study conducted in an academic medical center in the United States. Consecutive adult patients admitted with chronic liver disease were included. Patients were categorized into two groups based on whether they developed a VTE or not. The risk for VTE in each patient was evaluated using the Padua Predictor Score (PPS). Patients were risk stratified using the PPS score as high-risk (score ≥ 4) and low-risk (score < 4). The risk of VTE based on PPS categorization was evaluated using logistic regression.

Results

A total of 163 patients with liver disease were included in the study cohort. Of these, 18 (11%) developed VTE. Mean PPS was significantly greater in the VTE group than the non-VTE group (5.8 ± 2.0 versus 3.0 ± 2.1, respectively; p < 0.001). In high-risk patients 22% (n = 16/72) developed VTE and in low-risk patients 2% (2/91) developed VTE (p < 0.001). High-risk patients were more likely to have VTE (OR 12.7, 95% CI 2.8 to 57.4, p = 0.001).

Conclusion

The PPS is an effective risk assessment tool for VTE in patients hospitalized with chronic liver disease.     

Subcutaneous Enoxaparin for Therapeutic Anticoagulation in Hemodialysis Patients

Background

Information regarding dosing of low-molecular-weight heparins (LMWH) for therapeutic anticoagulation in hemodialysis (HD) patients is limited. The aim of this study was to retrospectively compare the safety and efficacy of enoxaparin versus unfractionated heparin (UFH) for therapeutic anticoagulation in HD patients.

Materials and Methods

This retrospective chart review evaluated HD patients treated with subcutaneous enoxaparin that were matched based on the indication for anticoagulation with patients treated with intravenous UFH to achieve therapeutic anticoagulation. Primary outcome measures included 30-day incidence of thromboembolic events and major bleeding. Secondary outcomes included rehospitalization within 30 days, length of stay, and mortality.

Results

One hundred sixty-four patients were evaluated, 82 in each group. The average daily dose of enoxaparin used to target therapeutic levels was 0.7 ± 0.2 mg/kg/day (range = 0.4-1). Comparing enoxaparin to UFH, there was no significant difference in major bleeding (6.1% vs 11%, p = 0.4) or thromboembolism (0% vs 2.4%, p = 0.5). Hospital length of stay was shorter in the enoxaparin group (20 ± 53.8 vs 28.9 ± 44.5 days, p = 0.02); there was no significant difference between groups in mortality or readmission. Adjusting for risk factors for bleeding there was a slight but statistically non-significant difference between enoxaparin versus UFH (OR = 0.77, 95%CI: 0.2-3.5, p = 0.73).

Conclusions

These findings suggest that therapeutic dosing of enoxaparin, in doses that ranged from 0.4-1 mg/kg/day, was as safe as intravenous UFH in providing therapeutic anticoagulation in stable patients requiring chronic hemodialysis.     

Renal failure as a risk factor for venous thromboembolism in critically Ill patients: A cohort study

Rationale

The relationship between kidney function and venous thromboembolism (VTE) in critically ill patients is not well studied. The main objective of this study was to evaluate this relationship in patients admitted to a medical-surgical intensive care unit (ICU).

Methods

This was a retrospective study of 798 patients admitted to a tertiary-care ICU and prospectively followed for the development of clinically suspected and radiologically diagnosed deep venous thrombosis or pulmonary embolism. Patients were divided based on admission creatinine and dialysis history into five groups: normal kidney function, RIFLE classes R, I and F (combined = acute kidney injury [AKI]) and endstage renal disease (ESRD). We compared VTE prophylaxis practices and VTE incidence in these groups and evaluated renal failure as a VTE risk factor using multivariate Cox regression analysis.

Results

Of the 798 patients, 27.2% had AKI and 10.1% had ESRD. Unfractionated heparin use was similar in the five groups but enoxaparin use was less frequent in AKI (13.4%) and ESRD (3.8%) patients compared with patients with normal kidney function (39.0%). VTE occurred in 7.6% of patients with normal renal function, 7.8% AKI patients and 2.5% ESRD patients (p = 0.22). The adjusted hazard ratios for VTE compared to patients with normal kidney function were 0.35 (95% confidence interval [CI], 0.08-1.47) for RIFLE class R, 1.19 (95% CI, 0.83-1.70) for RIFLE class I, 0.82 (95% CI, 0.59-1.14) for RIFLE class F and 0.71 (95% CI, 0.49-1.02, p = 0.06) for ESRD.

Conclusions

Neither AKI nor ESRD was an independent risk factors for critically ill patients.     

Increased thrombin generation in splanchnic vein thrombosis is related to the presence of liver cirrhosis and not to the thrombotic event

Introduction

In recent years there have been increasing evidence associating liver disease with hypercoagulability, rather than bleeding. The aim of the study was to evaluate the haemostatic potential in patients with liver disease.

Patients and methods

We measured thrombin generation in the presence and absence of thrombomodulin in patients with portal vein thrombosis (PVT, n = 47), Budd-Chiari syndrome (BCS, n = 15) and cirrhosis (n = 24) and compared the results to those obtained from healthy controls (n = 21). Fifteen patients with PVT and 10 patients with BCS were treated with warfarin and were compared to an equal number of patients with atrial fibrillation matched for prothrombin time-international normalized ratio. We assessed resistance to thrombomodulin by using ratios [marker measured in the presence/absence of thrombomodulin].

Results

There were no differences in thrombin generation between patients on warfarin treatment and their controls. Cirrhotic patients generated more thrombin in the presence of thrombomodulin and exhibited thrombomodulin resistance compared to controls [p = 0.006 for endogenous thrombin potential (ETP) and p < 0.001 for peak thrombin and both ratios ETP and peak] and patients with non-cirrhotic PVT (p = 0.001, p = 0.006, p < 0.001, p < 0.001 for ETP, peak, ratio ETP, ratio peak, respectively). The patients with cirrhotic PVT exhibited higher ETP (p = 0.044) and peak (p = 0.02) in the presence of thrombomodulin than controls, as well as thrombomodulin resistance (ETP and peak ratios: p = 0.001).

Conclusions

Hypercoagulability and thrombomodulin resistance in patients with cirrhosis were independent of the presence of splanchnic vein thrombosis. The hypercoagulability in patients with cirrhotic PVT could have implications for considering longer or more intensive treatment with anticoagulants in this group.     

Apolipoprotein M and the risk of unprovoked recurrent venous thromboembolism

Introduction

Apolipoprotein M (ApoM) protects against atherosclerosis; however, it is unknown whether it also protects against recurrent venous thromboembolism (VTE).

Material and Methods

Patients in the Malmö Thrombophilia Study (MATS) were followed post-anticoagulant treatment until the diagnosis of recurrent VTE or the end of the study (mean follow-up 36 months). Among patients with a first episode of unprovoked VTE, we identified 43 patients (9.7%) with recurrent VTE during the follow-up period. Three age- and sex-matched control subjects without recurrent VTE were selected for each case (n = 129). Plasma levels of ApoM were quantified by a sandwich ELISA method.

Results

Among all patients, the plasma levels (mean ± SD) of ApoM were not significantly different between patients with recurrent (0.70 ± 0.2) and non-recurrent VTE (0.74 ± 0.2), p = 0.2. However, after stratification of data according to gender, male patients with recurrent VTE showed significantly (p = 0.02) lower ApoM levels (0.63 ± 0.2) as compared to those with non-recurrent VTE (0.74 ± 0.2). No significant differences in ApoM levels were found between recurrent (0.8 ± 0.2) and non-recurrent VTE (0.75 ± 0.2) in female patients, p = 0.3. Cox-regression analysis showed that the risk of recurrent VTE was 0.98 (95% CI, 0.96-0.99) for each 0.01 μM increase in ApoM level in male patients (p = 0.042), and this risk remained unchanged after adjusting for inherited thrombophilia and body mass index (p = 0.027). ApoM levels were not associated with the risk of recurrent VTE in female patients.

Conclusion

Our results show that levels of ApoM in recurrent VTE may differ according to gender and lower levels of ApoM may predict VTE recurrence in male patients.     

The incidence and risk factors of recurrent venous thromboembolism during pregnancy

Introduction

Recurrent venous thromboembolism (VTE) during pregnancy is a challenging topic with relatively few publications. The aim of this study was to identify the incidence and the risk factors of recurrent antepartum VTE in women with a history of at least one previous VTE episode.

Materials and Methods

This observational cohort study involved 270 pregnant women (369 pregnancies) with at least one previous episode of VTE. The risk factors of recurrent antepartum VTE were identified by using group A (women without recurrent venous thromboembolism VTE) as a control group for group B (women with recurrent VTE despite LMWH (low molecular weight heparin) prophylaxis) and C (women with VTE recurrence in early pregnancy before the planned initiation of LMWH prophylaxis).

Results and Conclusions

The incidence of recurrent VTE was 7.6% (n = 28).Twelve recurrent VTEs in ten women (3.3%) developed during early pregnancy before initiation of LMWH and sixteen recurrent VTEs (4.3%) developed in 15 women despite LMWH prophylaxis.In women with recurrent antepartum VTE, the incidence of a history of two or more previous VTEs (group A vs. B: 5.7% vs. 40.0%, p < 0.001; group A vs. C: 5.7% vs. 30.0%, p = 0.022), previous VTE in connection with antiphospholipid antibody syndrome (group A vs. B: 2.6% vs. 20.0%, p = 0.012) and a history of VTE related to hormonal risk factors (group A vs. B: 60.4% vs. 93.3%, p = 0.011) was significantly higher compared to those with successful LMWH-prophylaxis. The percentage of the women with long-term anticoagulation was also significantly higher among the women with recurrent antepartum VTE (group A vs. B: 7.6% vs. 46.7%, p < 0.001) compared to those with successful LMWH-prophylaxis. The risk of antepartum recurrent VTE is considerable in women with a history of two or more previous VTEs, antiphospholipid antibody syndrome or long-term anticoagulation. The antepartum prophylaxis with prophylactic dose of LMWH or even with intermediate dose of LMWH might not be sufficient in this high-risk population.     

Incidental venous thromboembolism detected by PET-CT in patients with cancer: Prevalence and impact on survival rate

Introduction

People with cancer are at increased risk of incidental venous thromboembolism (VTE) and PET-CT imaging is commonly used in this population. However, the prevalence of incidental VTE detected by PET-CT in patients with cancer and its impact on survival are unknown.

Materials and Methods

This retrospective study was approved by the local Institutional Review Board. 1331 consecutive adult patients with cancer who underwent PET-CT examination between 2009 and 2012 were included in the study (mean age: 57 ± 15 years). PET-CT reports were reviewed to identify patients with incidental VTE at the time of examination. Survival rates were assessed with Kaplan-Meier curves. The Cox proportional hazards model was used to determine the association between incidental VTE and overall survival, after controlling for clinical variables.

Results

Incidental VTE was detected in 19 patients (1.4%). Patients with genitourinary malignancies, colorectal cancer and lung cancer had the highest rates of incidental VTE at PET-CT. At multivariate analysis, incidental VTE detected by PET-CT was associated with worse overall survival independently of patient age, hospitalization status at time of PET-CT examination, and the presence of metastatic disease (Hazard ratio = 2.03; 95% confidence interval = 1.08-3.81, p = 0.028).

Conclusion

Incidental VTE was detected in 1.4% of adult patients with cancer undergoing PET-CT imaging. Diagnosis of incidental VTE at PET-CT imaging was associated with worse overall survival in this population.     

A case series of LMWH use in pregnancy: Should trough anti-Xa levels guide dosing?

Introduction

Pregnancy is a thrombogenic state, increasing the risk for venous thromboembolism (VTE), and the risk of valve thrombosis amongst women with mechanical heart valves (MHV). While low molecular weight heparins (LMWH) are generally dosed based on weight (i.e., enoxaparin 1 mg/kg every 12 hours), data in pregnant women have shown that weight-based dosing does not consistently achieve target anti-Xa levels. In women with MHV, our practice includes titrating LMWH doses to target both trough and peak anti-Xa levels, while for those with VTE peak anti-Xa levels guide dosing.

Materials/Methods

This retrospective case series included pregnant women requiring LMWH treatment doses with at least 3 peak (+/− trough) anti-Xa levels. Our primary objective was to describe the actual LMWH dose required to achieve targeted anti-Xa levels relative to weight-based dosing in patients with MHV. Secondarily, we compared the same for VTE patients; compared actual dosing between those with MHV and VTE; and examined maternal and fetal outcomes.

Results/Conclusion

Women with MHV (N = 4) required greater than weight-based dosing of enoxaparin (1.35 mg/kg Q12H) to achieve targeted anti-Xa levels. Importantly, achieving target peak anti-Xa levels did not always ensure maintenance of minimum trough levels. VTE patients (N = 12) did not require more enoxaparin (0.96 mg/kg Q12H) than weight based dosing. MHV patients received more enoxaparin compared to VTE patients (P < 0.001). No bleeding or clotting complications were associated with LMWH administration. In pregnant women with MHV at high risk of thromboembolism, LMWH dosing guided by trough and peak anti-Xa levels should be considered.     

Meta-Analysis to Assess the Quality of International Normalized Ratio Control and Associated Outcomes in Venous Thromboembolism Patients

Introduction

Patients with venous thromboembolism (VTE) frequently require vitamin K antagonists (VKAs) to prevent recurrent events, but their use increases hemorrhage risk. We performed a meta-analysis to assess the quality of international normalized ratio (INR) control, identify study-level predictors of poor control and to examine the relationship between INR control and adverse outcomes in VTE patients.

Materials and Methods

We searched bibliographic databases (1990-June 2013) for studies of VTE patients receiving adjusted-dose VKAs that reported time in range (2.0-3.0) or proportion of INRs in range and/or reported INR measurements coinciding with thromboembolic or hemorrhagic events. Meta-analysis and meta-regression analysis was performed.

Results

Upon meta-analysis, studies found 59% (95%CI: 54-64%) of INRs measured and 61% (95%CI: 59-63%) of the time patients were treated were spent outside the target range of 2.0-3.0; with a tendency for under- versus over-anticoagulation. Moreover, this poor INR control resulted in a greater chance of recurrent VTE (beta-coefficient = -0.46, p = 0.01) and major bleeding (beta-coefficient = -0.30, p = 0.02). Patients with an INR < 2.0 made up 58% (95%CI: 39-77%) of VTE cases, while those with an INR > 3.0 made up 48% (95%CI: 34-61%) of major hemorrhage cases. Upon meta-regression, being VKA-naïve (-14%, p = 0.04) and treated in the community (-7%, p < 0.001) were associated with less time in range, while being treated in Europe/United Kingdom (compared to North America) was associated with (11%, p = 0.003) greater time.

Conclusions

Strategies to improve INR control or alternative anticoagulants, including the newer oral agents, should be widely implemented in VTE patients to reduce the rate of recurrent events and bleeding.     

Safety and Efficacy of Edoxaban,an Oral Factor Xa Inhibitor,Versus Enoxaparin for Thromboprophylaxis After Total Knee Arthroplasty: The STARS E-3 Trial

Introduction

This phase 3 trial compared the safety and efficacy of edoxaban, an oral direct factor Xa inhibitor, with enoxaparin sodium (enoxaparin) for thromboprophylaxis after total knee arthroplasty (TKA) in patients in Japan and Taiwan.

Materials and methods

In this randomized, double-blind, double-dummy study, patients received oral edoxaban 30 mg once daily beginning 6 to 24 hours postsurgery or enoxaparin 2000 IU (equivalent to 20 mg) subcutaneously twice daily beginning 24 to 36 hours postsurgery for 11 to 14 days. The primary efficacy endpoint was the composite of symptomatic pulmonary embolism and symptomatic and asymptomatic deep vein thrombosis. Safety endpoints included the incidence of major bleeding, clinically relevant non-major (CRNM) bleeding, major bleeding or CRNM bleeding, all bleeding events, adverse events, and adverse drug reactions.

Results

Of 716 patients enrolled, 360 and 356 were randomized to receive edoxaban or enoxaparin, respectively. The primary efficacy outcome occurred in 22/299 (7.4%) and 41/295 (13.9%) patients in the edoxaban and enoxaparin groups, respectively (relative risk reduction = 46.8%), indicating non-inferiority (P < 0.001) and superiority (P = 0.010) of edoxaban versus enoxaparin. In the edoxaban and enoxaparin groups, major bleeding occurred in 4/354 (1.1%) versus 1/349 (0.3%) patients (P = 0.373); major or CRNM bleeding occurred in 22/354 (6.2%) versus 13/349 (3.7%) patients (P = 0.129), respectively.

Conclusions

Edoxaban 30 mg once daily was more effective for thromboprophylaxis than subcutaneous enoxaparin 2000 IU twice daily following TKA and demonstrated a similar incidence of bleeding events.     

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.     

Factors associated with the development of superficial vein thrombosis in patients with varicose veins

Introduction

Superficial vein thrombosis (SVT) is a common and controversial clinical entity. Recent studies have demonstrated that SVT should be seen as a venous thromboembolism (VTE). The objective of this study was to investigate the prevalence of thrombophilia defects and to estimate the role of age, sex and body mass index (BMI) in patients with varicose veins (VVs) and SVT.

Materials and Methods

A total of 230 patients with VVs, 128 with, and 102 without SVT underwent thrombophilia testing included factor V Leiden, prothrombin G20210A, methylenetetrahydrofolate reductase and plasminogen activator inhibitor- 1 mutations, protein C, protein S (PS), anti-thrombin III and plasminogen deficiencies and levels of A₂ antiplasmin, activate protein C resistance and lupus anticoagulant. According to Clinical- Etiology- Anatomy- Pathophysiology (CEAP) classification patients were categorized in two subgroups: moderate disease (C_2,3) and severe disease (C_4,5,6). Age and body mass index were also assessed.

Results

The prevalence of thrombophilia defects was significantly higher in patients with moderate disease and SVT (p = 0.002). In the C_2,3 group, SVT was associated with PS deficiency (p = 0.018), obesity (p < 0.001), male gender (p = 0.047) and age (p < 0.001). There were no significant differences in patients with severe disease.

Conclusions

Age, male sex, obesity and PS deficiency are factors associated with SVT development among patients with VVs having moderate disease (C_2,3).     

Influence of coronary artery disease-associated genetic variants on risk of venous thromboembolism

Introduction

We investigated whether genetic variations robustly associated with coronary artery disease are also associated with risk of venous thromboembolism in a well-defined, female case–control study (n = 2753) from Sweden.

Materials and Methods

39 single nucleotide polymorphisms in 32 loci associated with coronary artery disease in genome-wide association studies were identified in a literature search and genotyped in the ThromboEmbolism Hormone Study (TEHS). Association with venous thromboembolism was assessed by logistic regression.

Results

Only rs579459 in the ABO locus demonstrated a significant association with VTE. A tentative association between ANRIL and VTE in the discovery analysis failed to replicate in a meta-analysis of 4 independent cohorts (total n = 7181).

Conclusions

It appears that only the ABO locus is a shared risk factor for coronary artery disease and VTE.     

The study of the thrombin generation mechanism and the effect of low molecular weight heparin as thromboprophylaxis in patients undergoing total knee and hip replacement

Introduction

The recommended duration of post-operative Low-Molecular-Weight-Heparins (LMWHs) thromboprophylaxis in Total-Hip-Replacement (THR) and Total-Knee-Replacement (TKR) surgery is controversial.Our aim is to study the thrombin generation (TG) modifications induced by surgery and to evaluate the effect of LMWH on TG during and after the recommended duration.

Patients/Methods

Thirty-one patients received 4000 IU anti-Xa/day of enoxaparin, 8-hours post-operatively (15 THR for 30-days and 16 TKR for 15-days). TG assay sensitive to enoxaparin was performed, pre-operatively (D0), 7-hours post-surgery (D1), 8-days post-surgery (D8), and 2-days after thromboprophylaxis withdrawal (D32 and D17), evaluating: lag-time, endogenous thrombin potential (ETP), peak amount of generated thrombin (Peak), time-to-Peak (tt-Peak), and the Mean-Rate-Index [MRI = Peak/(tt-Peak–lag-time)].

Results

TKR surgery decreased lag-time and tt-Peak and increased MRI on D1 vs D0 (p < 0.05). In contrast, THR did not significantly modify TG. Enoxaparin effectively reduced thrombin generation in both groups. Thromboprophylaxis withdrawal resulted in rebound increase of TG in the TKR patients (ETP, Peak & MRI significantly increased on D17 vs D0; p < 0.05, and vs. D1; p < 0.05) but not in THR patients. Variability in the response to enoxaparin was observed among patients of the same group.

Conclusions

TKR surgery is more thrombogenic than THR surgery. In THR patients TG was efficiently inhibited by 30-day thromboprophylaxis, whereas, in TKR patients treated for 15-days TG was not effectively inhibited. Individual variability of the response to enoxaparin was observed in both groups revealing some form of biological resistance to enoxaparin. TG assay may represent the breakthrough step to efficient antithrombotic strategy in clinical settings with high thrombotic risk.     

Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: A pooled analysis of three trials

Background

Three randomized, double-blind trials compared dabigatran, an oral direct thrombin inhibitor, with enoxaparin for the primary prevention of venous thromboembolism (VTE) in patients undergoing elective total hip and knee arthroplasty.

Objectives and Methods

We conducted a pre-specified pooled analysis of these trials. 8,210 patients were randomized, of whom 8,135 were treated (evaluable for safety) with dabigatran 220 mg or 150 mg once-daily, or subcutaneous enoxaparin (40 mg once-daily or 30 mg twice-daily). Efficacy analyses were based on the modified intention-to-treat population of 6,200 patients with an evaluable outcome. The common risk difference (RD) of treatment effect between each dabigatran dose and enoxaparin was estimated using fixed-effects models, and statistical heterogeneity was estimated using the I² statistic.

Results

The composite outcome of major VTE (proximal deep vein thrombosis and/or pulmonary embolism) and VTE-related mortality occurred in 3.3% of the enoxaparin group versus 3.0% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, 95% CI -1.3% to 0.9%, I² = 37%) and 3.8% of the 150 mg group (RD vs. enoxaparin 0.5%, -0.6% to 1.6%, I² = 0%). Major bleeding occurred in 1.4% of the enoxaparin group versus 1.4% of the dabigatran 220 mg group (RD vs. enoxaparin -0.2%, -0.8% to 0.5%, I² = 40%) and 1.1% of the 150 mg group (RD vs. enoxaparin -0.4%, -1.0% to 0.2%, I² = 0%).

Conclusions

Oral dabigatran was as effective as subcutaneous enoxaparin in reducing the risk of major VTE and VTE-related mortality after hip or knee arthroplasty and has a similar bleeding profile.     

P-selectin/ PSGL-1 Inhibitors versus enoxaparin in the resolution of venous thrombosis: A meta-analysis

Background

P-selectin antagonism has been shown to decrease thrombogenesis and inflammation in animal models of deep venous thrombosis (DVT).

Objective

To determine the effectiveness of P-selectin inhibitors versus saline and enoxaparin in venous thrombus resolution in nonhuman primate models of venous thrombosis.

Methods

Studies reporting vein re-opening, inflammation expressed as Gadolinium enhancement and coagulation parameters were searched in the literature and pooled into a meta-analysis using an inverse variance with random effects.

Results

Five studies were identified comparing P-selectin/ PSGL-1 inhibitors versus saline or enoxaparin regarding venous thrombosis resolution. Vein re-opening was significantly higher on P-selectin/ PSGL-1 compounds, when compared to saline (Inverse Variance [IV] 95% CI; 44.37 [17.77^_70.96], p = 0.001, I² = 97%) and similar to enoxaparin (IV 95% CI; 5.03 [-8.88^_18.95], p = 0.48, I² = 41%). Inflammation, reflected as Gadolinium enhancement at magnetic resonance venography (MRV), was significantly decreased in the P-selectin treated group when compared to saline (IV 95% CI; -17.84 [-14.98 ^_ -8.30], p < 0.00001, I² = 80%). No significant differences on vein wall inflammation were observed between P-selectin/ PSGL-1 inhibitors and enoxaparin treated animals (IV95% CI; -3.59 [-10.67^_3.48], p = 0.32, I² = 66%). In addition, there was no differences in the coagulation parameters (aPTT, TCT, BT, D-Dimer, fibrinogen, platelets) between P-selectin/ PSGL-1 inhibitors and enoxaparin (IV 95% CI; -1.12[-2.36^_0.11], p = 0.07, I² = 92%), although there was a trend showing less of a prolongation in TCT with P-selectin/PSGL-1 inhibitors compared to enoxaparin (p < 0.0001).

Conclusion

P-selectin antagonism successfully paralleled the low-molecular-weight-heparin enoxaparin, for the treatment of DVT in nonhuman primate models, by decreasing both thrombus burden and inflammation without causing any bleeding complications and without increasing coagulation times.