Mechanisms and mitigating factors for venous thromboembolism in chronic kidney disease: the REGARDS study

Essentials

• Chronic kidney disease (CKD) is associated with procoagulant and inflammatory biomarkers.
• We studied the association of CKD and venous thromboembolism (VTE) in a case‐cohort study.
• Factor VIII, D‐dimer and C‐reactive protein appeared to explain the association of CKD and VTE.
• Statin use was protective against VTE in those with and without CKD.

Summary

Background

Chronic kidney disease (CKD) is associated with venous thromboembolism (VTE) risk via unknown mechanisms. Whether factors associated with reduced VTE risk in the general population might also be associated with reduced VTE risk in CKD patients is unknown.

Objectives

To determine whether thrombosis biomarkers attenuate VTE risk, and whether factors associated with reduced VTE risk are similarly effective in CKD patients.

Methods

Baseline biomarkers were measured in a cohort (294 VTE cases; 939 non‐cases) from the Reasons for Geographic and Racial Differences in Stroke (REGARDS) study, a nationwide prospective cohort study of 30 239 persons aged ≥45 years with 4.3 years of follow‐up. The hazard ratio (HR) of VTE per 10 mL min^?1 1.73 m^?2 decrease in estimated glomerular filtration rate (eGFR), and the percentage attenuation of this HR by each biomarker, were calculated. Associations of protective factors (physical activity, lower body mass index [BMI], and aspirin, warfarin and statin use) with VTE were estimated in those with and without CKD.

Results

The HR for VTE with lower eGFR was 1.13 (95% confidence interval [CI] 1.02–1.25), and VTE risk was attenuated by 23% (95% CI 5–100) by D‐dimer, by 100% (95% CI 50–100) by factor VIII, and by 15% (95% CI 2–84) by C‐reactive protein. Normal BMI was associated with lower VTE risk in those without CKD (HR 0.47, 95% CI 0.32–0.70), but not in those with CKD (HR 1.07, 95% CI 0.51–2.22). Statin use, physical activity and warfarin use were associated with lower VTE risk in both groups.

Conclusions

Procoagulant and inflammatory biomarkers mediated the association of eGFR with VTE. Higher physical activity, statin use and warfarin use mitigated VTE risk in those with CKD and those without CKD, but normal BMI did not mitigate VTE risk in CKD patients.

     

Citrullinated histone H3, a biomarker of neutrophil extracellular trap formation,predicts the risk of venous thromboembolism in cancer patients

Essentials

• Neutrophil extracellular traps (NETs) might play a role in cancer‐related coagulopathy.
• We determined NET biomarkers and followed cancer patients for venous thromboembolism (VTE).
• We found a constant association with VTE for citrullinated histone H3.
• Biomarkers of NET formation could reflect a novel pathomechanism of cancer‐related VTE.

Summary

Background

Neutrophil extracellular traps (NETs) are decondensed chromatin fibers that might play a role in the prothrombotic state of cancer patients.

Objectives

To investigate whether the levels of citrullinated histone H3 (H3Cit), a biomarker for NET formation, cell‐free DNA (cfDNA) and nucleosomes predict venous thromboembolism (VTE) in cancer patients.

Patients/Methods

Nine‐hundred and forty‐six patients with newly diagnosed cancer or progression after remission were enrolled in this prospective observational cohort study. H3Cit, cfDNA and nucleosome levels were determined at study inclusion, and patients were followed for 2 years. VTE occurred in 89 patients; the cumulative 3‐month, 6‐month, 12‐month and 24‐month incidence rates of VTE were 3.7%, 6.0%, 8.1%, and 10.0%, respectively.

Results

Patients with elevated H3Cit levels (> 75th percentile of its distribution, n = 236) experienced a higher cumulative incidence of VTE (2‐year risk of 14.5%) than patients with levels below this cut‐off (2‐year risk of 8.5%, n = 710). In a competing‐risk regression analysis, a 100 ng mL^?1 increase in H3Cit level was associated with a 13% relative increase in VTE risk (subdistribution hazard ratio [SHR] 1.13, 95% confidence interval [CI] 1.04–1.22). This association remained after adjustment for high VTE risk and very high VTE risk tumor sites, D‐dimer level, and soluble P‐selectin level (SHR 1.13, 95% CI 1.04–1.22). The association of elevated nucleosome and cfDNA levels with VTE risk was time‐dependent, with associations with a higher risk of VTE only during the first 3–6 months.

Conclusion

These data suggest that biomarkers of NET formation are associated with the occurrence of VTE in cancer patients, indicating a role of NETs in the pathogenesis of cancer‐associated thrombosis.

     

Risk stratification for the development of venous thromboembolism in hospitalized patients with cancer

Essentials

• The Khorana score is validated for risk of venous thromboembolism (VTE) in cancer outpatients.
• We conducted a multicenter analysis of medically hospitalized cancer patients.
• Patients with a higher Khorana score on admission were more likely to develop VTE.
• The Khorana score is predictive of in‐hospital, symptomatic VTE development.

Summary

Introduction

The Khorana score is a validated risk assessment score for estimating the risk of symptomatic venous thromboembolism (VTE) in outpatients with cancer. The objective of this study was to assess the Khorana score for predicting the development of VTE in cancer patients during hospital admission.

Methods

We conducted an analysis of consecutive, adult cancer patients hospitalized for medical reasons between January and June 2010 in three academic medical centers. Information on objectively diagnosed, symptomatic VTE during hospitalization, use of anticoagulant thromboprophylaxis (TP) and Khorana score variables at the time of admission was collected.

Results

A total of 1398 patients were included. Mean age was 62 years, 51.2% were male, and mean BMI was 25.9 kg m^?2. The most frequent reasons for hospitalization were chemotherapy administration (22.3%), followed by pain control and palliation (21.4%). The overall incidence of VTE was 2.9% (95% CI, 2.0–3.8%), occurring in 5.4% (95% CI, 1.9–8.9%) of the high‐, 3.2% (95% CI, 2.0–4.4%) of the intermediate‐ and 1.4% (95% CI, 0.3–2.6%), of the low‐risk groups. High‐risk patients were more likely than low‐risk patients to have VTE (OR, 3.9; 95% CI, 1.4–11.2).

Conclusion

The Khorana score is predictive of in‐hospital, symptomatic VTE development in cancer patients who are hospitalized for medical reasons and may be a useful tool for tailoring inpatient anticoagulant thromboprophylaxis.

     

Mild antithrombin deficiency and risk of recurrent venous thromboembolism: results from the MEGA follow‐up study

Essentials

• Mild antithrombin deficiency may increase the risk of recurrent venous thromboembolism (VTE).
• In a cohort study, we stratified patients with VTE to various cut‐off antithrombin levels.
• A 1.6–3.7‐fold increased risk of recurrent VTE was observed in the lowest antithrombin categories.
• Mild antithrombin deficiency (activity < 5th percentile of normal) increases recurrent VTE risk.

Summary

Background

Mild antithrombin deficiency (previously defined as antithrombin activity below 70% or 80%) has been associated with a 2.4–3.5‐fold increased risk of recurrent venous thromboembolism (VTE). This finding may have implications for duration of antithrombotic therapy in VTE patients with mild antithrombin deficiency.

Objectives

To externally validate whether mild antithrombin deficiency is a risk factor for recurrent VTE.

Methods

In a population‐based cohort study, patients with a first VTE (n = 2357) were stratified according to percentile cut‐off antithrombin levels (< 5th [< 87%], 5–10th [87–92%], > 10th percentile [> 92%]) and functional antithrombin levels (< 70%, 70–80%, > 80%).

Results

During a median follow‐up of 7.4 years, 361 recurrent events occurred (incidence rate, 2.5/100 patient‐years). We observed an increased risk of recurrent VTE in the lowest antithrombin activity category (< 5th percentile; < 87%) as compared with antithrombin activity that was > 10th percentile (> 92%), with an adjusted hazard ratio (HR) of 1.5 (95%CI, 1.0–2.3). When analyses were stratified to antithrombin cut‐off criteria of< 70% vs. patients with antithrombin activity > 80%, the adjusted HR for venous recurrence was 3.7 (95% CI, 1.4–9.9). Mild antithrombin deficiency was able to predict recurrent VTE over at least 8 years of follow‐up and the association remained present when the population was stratified to the presence or absence of thrombosis risk factors. Restriction analyses, where patients who used anticoagulation at time of blood draw and those who reported drinking ≥ 5 glasses alcohol daily were excluded, did not materially affect these outcomes.

Conclusion

This study confirms that mild antithrombin deficiency is a risk factor for recurrent VTE.

     

Outcomes following a negative computed tomography pulmonary angiography according to pulmonary embolism prevalence: a meta‐analysis of the management outcome studies

Essentials

• Computed tomographic pulmonary angiography (CTPA) is used to exclude pulmonary embolism.
• This meta‐analysis explores the occurrence of venous thromboembolic events (VTE) after a CTPA.
• Occurrence of VTE after a negative CTPA is ?8% in study subgroups with a prevalence of PE ≥ 40%.
• CTPA may be insufficient to safely rule out VTE as a stand‐alone diagnostic test for this subgroup.

Summary

Background

Outcome studies have reported the safety of computed tomographic pulmonary angiography (CTPA) as a stand‐alone imaging technique to rule out pulmonary embolism (PE). Whether this can be applied to all clinical probabilities remains controversial.

Objectives

We performed a meta‐analysis to determine the proportion of patients with venous thromboembolic events (VTE) despite a negative CTPA according to pretest PE prevalence.

Methods

We searched MEDLINE, EMBASE and the Cochrane Library (January 1990 to May 2017) for outcome studies recruiting patients with suspected PE using CTPA as a diagnostic strategy. The primary outcome was the cumulative occurrence of VTE at 3 months following a negative CTPA.

Results

Twenty‐two different studies were identified. VTE was confirmed in 2.4% of patients (95% CI, 1.3–3.8%) either at the time of the index event or in the 3 months follow‐up. Subgroup analyses suggested that the cumulative occurrence of VTE was related to pretest prevalence of PE, as VTE occurred in 1.8% (95% CI, 0.5–3.7%), 1.4% (95% CI, 0.7–2.3%), 1.0% (95% CI, 0.5–1.8%) and 8.1% (95% CI, 3.5–14.5%) of subgroups of patients with a PE prevalence < 20%, 20–29%, 30–39% and ≥ 40%, respectively. This was further confirmed using meta‐regression analysis.

Conclusions

The negative predictive value of CTPA for VTE varies according to pretest prevalence of PE, and is likely to be insufficient to safely rule out VTE as a stand‐alone diagnostic test amongst patients at the highest pretest probability of VTE. Prospective studies are required to validate the appropriate diagnostic algorithm for this subgroup of patients.

     

Longitudinal increases in blood biomarkers of inflammation or cardiovascular disease and the incidence of venous thromboembolism

Essentials

• Inflammatory and cardiac diseases are associated with increased venous thromboembolism (VTE) risk.
• Our prospective study assessed rise in inflammatory or cardiac biomarkers and VTE risk.
• A greater 6‐year rise in N‐terminal natriuretic peptide is associated with increased VTE incidence.
• Volume overload or impending cardiac disease may contribute to VTE occurrence.

Summary

Background

We previously showed that participants in the population‐based Atherosclerosis Risk in Communities (ARIC) cohort with elevated levels of blood biomarkers of inflammation or cardiac disease were at increased risk of venous thromboembolism (VTE).

Objective

We hypothesized that ARIC participants with larger 6‐year increases in the levels of three biomarkers – C‐reactive protein (CRP), N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP), and troponin T – would also have an increased subsequent risk of VTE.

Methods

We measured changes in the levels of these biomarkers in 9844 participants from 1990–1992 to 1996–1998, and then identified VTEs through 2015.

Results

A greater 6‐year rise in the level of NT‐proBNP, but not in that of CRP or troponin T, was significantly associated with increased VTE incidence over a median of 17.6 years of follow‐up. After adjustment for other VTE risk factors, those whose NT‐proBNP level rose from < 100 pg mL^?1 to ≥ 100 pg mL^?1 had a hazard ratio for VTE of 1.44 (95% confidence interval [CI] 1.15–1.80), as compared with the reference group with an NT‐proBNP level of < 100 pg mL^?1 at both times. This hazard ratio was slightly higher (1.66, 95% CI 1.19–2.31) during the first 10 years of follow‐up, but was attenuated (1.24, 95% CI 0.99–1.56) after adjustment for prevalent and incident coronary heart disease, heart failure, and atrial fibrillation.

Conclusions

The two most likely explanations for our results are that: (i) an increasing NT‐proBNP level reflects increasing subclinical volume overload and potentially increased venous stasis or subclinical PE that had gone unrecognized over time; or (ii) an increasing NT‐proBNP level is a risk marker for impending cardiac disease that places patients at risk of VTE.

     

Venous thromboembolism in patients with liver diseases

Essentials

• Emerging evidence shows that patients with liver disease are not protected from thrombotic events.
• We assessed the risk of venous thromboembolism (VTE) in patients with liver disease.
• The presence of VTE resulted in an increase in mortality for patients with liver disease.
• Hospitalized patients with moderate‐severe liver disease had low risk of VTE during admission.

Summary

Background and Aims

Patients with liver disease were traditionally believed to be protected against development of blood clots, but some studies have shown a potential increased risk of venous thrombotic complications. We assessed the risk of venous thromboembolism (VTE) in patients with liver disease.

Methods

Data in discharge reports of patients with liver disease and control patients without liver disease were analyzed from the national inpatient sample. Incidence of VTE was compared in patients with mild, moderate‐severe or no liver disease, and the impact on in‐hospital mortality and length of stay was calculated.

Results

The overall incidence of VTE for patients with no liver disease, mild liver disease and moderate‐severe liver disease was 2.7, 2.4 and 0.9 per 100 patient discharges, respectively. In the presence of VTE, in‐hospital mortality was 10.8%, 5.8%, and 21.7% for the no liver disease, mild disease and moderate‐severe liver disease, respectively. The presence of VTE resulted in an increase in mortality for patients with no liver disease (OR, 1.16; 95% CI, 1.14–1.18) and moderate‐severe liver disease (OR, 1.63; CI 95%, 1.42–1.88).

Conclusions

Patients with moderate‐severe liver disease have a lower risk of VTE than those without liver disease. Development of thrombosis during admission increased the risk of in‐hospital mortality.

     

Reliability of hemostasis biomarkers is affected by time‐dependent intra‐patient variability

Essentials

• Nucleosomes and free DNA are two newly described biomarkers in venous thromboembolism (VTE).
• Reliability of nucleosomes, plasma free DNA and conventional hemostasis markers were studied.
• Hemostasis biological parameters vary over a short time‐frame in VTE patients.
• Hemostasis biological parameters also vary over a short time‐frame in healthy controls.

Summary

Background

Previous studies have associated neutrophil‐derived circulating nucleosomes and plasma free DNA with venous thromboembolism (VTE). However, there are few data concerning these two biomarkers and no studies have compared the reliability of nucleosomes and plasma free DNA against that of conventional hemostasis markers.

Objectives

We performed a 3‐year prospective study of nucleosomes and plasma free DNA levels in comparison with conventional hemostatic biomarkers and blood cells.

Patients/Methods

Fifteen healthy controls and 22 randomly selected patients with a history of VTE were followed monthly for 6 months. The reliability of these markers was evaluated by the intraclass correlation coefficient (ICCs).

Results and Conclusions

In healthy controls and patients, we found a low reliability for nucleosomes and plasma free DNA, with ICCs at 0.538 (95% confidence interval [CI], 0.334–0.764) and 0.091 (95% CI, ?0.026–0.328), respectively, in the healthy controls, and at 0.213 (95% CI, 0.042–0.463) and 0.161 (CI 95%, 0.008–0.398) in the patient group. For the conventional hemostasis biomarkers and for blood cells, reliability ranged from poor to good in the healthy volunteers and from poor to acceptable in the patient group. Our study shows for the first time that hemostasis biological parameters spontaneously vary over a short time‐frame in VTE patients and, more surprisingly, in normal individuals. The clinical value of such intra‐individual variations is currently unknown. This variability might mean reinterpreting diagnostic or prognostic models based on static evaluation of individuals. Studying the intrinsic value of individual patterns of markers’ variability is warranted.

     

Impact of time since diagnosis and mortality rate on cancer‐associated venous thromboembolism: the Scandinavian Thrombosis and Cancer (STAC) cohort

Essentials

• Competing risk by death may lead to overestimation of venous thromboembolism (VTE) risk in cancers.
• We assessed the risk of VTE in cancer with and without accounting for competing risk by death.
• The risk of VTE was influenced by the mortality rate and the time since cancer diagnosis.
• Competing risk by death should be taken into account when exploring VTE risk in cancer.

Summary

Background

Venous thromboembolism (VTE) is a common complication in cancer, and studies have suggested that aggressive cancers create the highest risk of VTE. However, competing risk by death may result in overestimation of VTE risk in patients with cancers associated with high mortality. Therefore, we estimated the risk of VTE by cancer site, accounting for the differential mortality between cancers.

Methods

The Scandinavian Thrombosis and Cancer cohort included 144 952 participants followed from 1993–1997 to 2008–2012. Incidence rates, cause‐specific hazard ratios (HRs) and subdistribution HRs (SHRs) were assessed for overall cancer and by cancer site according to time intervals since cancer diagnosis.

Results

During follow‐up, 14 272 subjects developed cancer, and 567 had cancer‐related VTE. In cause‐specific analyses, the VTE risk was highest in the first 6 months after cancer diagnosis (HR 17.5, 95% confidence interval [CI] 15.1–20.3), and declined rapidly thereafter. However, when mortality was taken into account, the risk was similar in the periods 6 months before (SHR 4.8, 95% CI 3.6–6.4) and 6 months after (SHR 4.6, 95% CI 3.9–5.4) cancer diagnosis. The range of the 2‐year cumulative VTE incidence rates was substantially narrowed for all cancer sites after competing risk by death was taken into account (from 1–10% to 1–4%).

Conclusion

VTE risk by cancer site was influenced by the mortality rate and the time since cancer diagnosis. Our findings suggest that the cancer itself is a major contributor to VTE risk, and that competing risk by death should be taken into account when VTE risk in cancer is explored.

     

Elevated plasma levels of P‐selectin glycoprotein ligand‐1‐positive microvesicles in patients with unprovoked venous thromboembolism

Essentials

• PSGL‐1⁺ microvesicles (MVs) may be important in venous thromboembolism (VTE).
• We measured plasma levels and parental origin of PSGL‐1⁺ MVs in patients with unprovoked VTE.
• VTE patients had higher plasma levels of PSGL‐1⁺ MVs than healthy controls.
• The PSGL‐1⁺ MVs originated mainly from monocytes and endothelial cells.

Summary

Background

Microvesicles (MVs) express antigens from their parental cells and have a highly procoagulant surface. Animal studies suggest that P‐selectin glycoprotein ligand‐1‐positive (PSGL‐1⁺) MVs play a role in the pathogenesis of venous thromboembolism (VTE).

Objective

The aim of this study was to determine plasma levels, the cellular origin and the morphological characteristics of PSGL‐1⁺ MVs in patients with unprovoked VTE.

Methods

We conducted a population‐based case–control study in 20 patients with a history of unprovoked VTE and 20 age‐ and sex‐matched healthy controls recruited from the general population. Plasma levels, the cellular origin and the morphological characteristics of PSGL‐1⁺ MVs were evaluated using flow cytometry, electron microscopy and confocal microscopy.

Results

Plasma levels of PSGL‐1⁺ MVs were associated with increased risk of VTE. The odds ratio per one standard deviation increase in PSGL‐1⁺ MVs was 3.11 (95% confidence interval [CI], 1.41–6.88) after adjustment for age and sex, and 2.88 (95% CI, 1.29–6.41) after further adjustment for body mass index. The PSGL‐1⁺ MVs originated mainly from monocytes and endothelial cells determined by double staining with markers of parental cells using flow cytometry and transmission electron microscopy. Scanning electron microscopy of PSGL‐1‐labeled plasma‐derived MVs displayed dominantly spherical vesicles that varied between 50 and 300 nm in diameter.

Conclusions

Increased plasma levels of PSGL‐1⁺ MVs are associated with the risk of unprovoked VTE. Large population‐based prospective studies are required to validate our findings.

     

Rivaroxaban for thromboprophylaxis among patients recently hospitalized for acute infectious diseases: a subgroup analysis of the MAGELLAN study

Essentials

• Net benefit of venous thromboprophylaxis (VTE) in patients hospitalized for infections is unknown.
• MAGELLAN trial subgroup analysis was performed for patients hospitalized for acute infectious diseases.
• At day 35, prolonged rivaroxaban prophylaxis reduced VTE compared to enoxaparin (4.2% vs. 6.6%).
• Rivaroxaban prophylaxis reduced VTE in patients hospitalized for active lung infections.

Summary

Background

Despite the well‐established association between infection and venous thromboembolism (VTE), there are few data specifically assessing the efficacy and safety of the VTE prophylaxis strategies for patients hospitalized for acute infectious diseases.

Objectives

To estimate the incidence of VTE and bleeding outcomes, comparing prolonged prophylaxis with rivaroxaban 10 mg daily for 35 days with enoxaparin 40 mg daily for 10 days.

Patients/Methods

A subgroup analysis of patients hospitalized for acute infectious diseases in the MAGELLAN trial was performed. The primary efficacy outcome was the composite of asymptomatic proximal or symptomatic VTE at days 10 and 35. The principal safety outcome was the composite of major or clinically relevant non‐major bleeding.

Results

Three thousand one hundred and seventy‐three patients with acute infectious diseases leading to hospitalization were randomized to either rivaroxaban (n = 1585) or enoxaparin/placebo (n = 1588), and received at least one dose of study medication. At day 10, primary composite efficacy outcomes did not differ between prophylaxis strategies (rivaroxaban, 2.7%; and enoxaparin, 3.7%). At day 35, there were fewer VTE events with rivaroxaban (4.2%) than with enoxaparin (6.6%) (relative risk [RR] 0.64; 95% confidence interval [CI] 0.45–0.92). Patients with pulmonary infections randomized to rivaroxaban had a lower incidence of VTE both at 10 days (RR 0.50, 95% CI 0.28–0.90) and at 35 days (RR 0.54, 95% CI 0.33–0.87). Primary safety outcome events were increased with rivaroxaban (RR 2.42, 95% CI 1.60–3.66).

Conclusions

Prolonged rivaroxaban prophylaxis reduced the incidence of VTE in patients hospitalized for acute infectious diseases, particularly those involving the lungs. Efficacy benefits were, in part, offset by bleeding outcomes. ClinicalTrials.gov Number: NCT 00571649.

     

Clinical course of patients with symptomatic isolated superficial vein thrombosis: the ICARO follow‐up study

Essentials

• Late sequelae of isolated superficial vein thrombosis (iSVT) have rarely been investigated.
• We studied 411 consecutive outpatients with acute iSVT with a median follow‐up of three years.
• Male sex and cancer are risk factors for future deep vein thrombosis or pulmonary embolism.
• Patients without cancer appear to be at a negligible risk for death.

Summary

Background

Studies of long‐term thromboembolic complications and death following acute isolated superficial vein thrombosis (iSVT) of the lower extremities are scarce.

Objectives

To investigate the course of iSVT in the setting of an observational multicenter study.

Methods

We collected longitudinal data of 411 consecutive outpatients with acute, symptomatic, objectively diagnosed iSVT who were previously included in the cross‐sectional ICARO study. Four patients followed for < 30 days and 79 with concomitant deep vein thrombosis (DVT) or pulmonary embolism (PE) were excluded from the present analysis. The primary outcome was symptomatic DVT or PE. The safety outcomes were major bleeding and all‐cause death.

Results

The median follow‐up time was 1026 days (interquartile range 610–1796). Symptomatic DVT/PE occurred in 52 (12.9%) patients, giving annualized rates of 1.3% (95% confidence interval [CI] 0.3–3.9%) on anticoagulant treatment and 4.4% (95% CI 3.2–5.8%) off anticoagulant treatment. Male sex (adjusted hazard ratio [HR] 2.03 [95% CI 1.16–3.54]) and active solid cancer (adjusted HR 3.14 [95% CI 1.11–8.93]) were associated with future DVT/PE, whereas prior DVT/PE failed to show significance, most likely because of bias resulting from prolonged anticoagulant treatment. Three major bleeding events occurred on treatment, giving an annualized rate of 1.4% (95 CI 0.3–4.0%). Death was recorded in 16 patients (annualized rate: 1.1% [95% CI 0.6–1.7%]), and was attributable to cancer (n = 8), PE (n = 1), cardiovascular events (n = 3), or other causes (n = 4).

Conclusions

The long‐term risk of DVT/PE after anticoagulant discontinuation for acute iSVT is clinically relevant, especially in males and in the presence of active cancer. The risk of death appears to be negligible in patients without cancer.     

Reduction in physical function in women after venous thromboembolism

Essentials

• The association of venous thromboembolism (VTE) with subsequent physical function remains unclear.
• We prospectively evaluated this relationship among women from the Nurses’ Health Studies.
• We found a decline in physical function over four years in women with incident VTE.
• This decline was somewhat greater among women specifically reporting a pulmonary embolism.

Summary

Background

Physical function is integral to healthy aging; however, limited research has examined the association of venous thromboembolism(VTE) with subsequent physical function.

Objectives

To prospectively evaluate the relationship between VTE and decline in physical function among 80 836 women from the Nurses’ Health Study(NHS), ages 46–72 in 1992, and 84 304 women from the Nurses’ Health Study II(NHS II), ages 29–48 in 1993.

Methods

Physical function was measured by the Medical Outcomes Short Form‐36 physical function scale, administered every 4 years. We compared change in physical function for women with vs. without an incident VTE in each 4‐year follow‐up period using multivariable linear regression.

Results

We observed a decline in physical function over 4 years when comparing women with vs. those without incident VTE in both older (NHS) and younger (NHS II) women (multivariable‐adjusted mean difference NHS, ?6.5 points [95% CI ?7.4, ?5.6] per 4 years; NHS II, ?3.8 [95% CI ?5.6, ?2.0]). This difference appeared greater among women specifically reporting a pulmonary embolism (NHS, ?7.4 [95% CI ?8.7, ?6.1]; NHS II, ?4.8 [95% CI ?6.8, ?2.8]), and was equivalent to 6.2 years of aging. Whereas longer‐term slopes of physical function decline following a VTE were not different from the slopes of decline in women without a VTE, the absolute level of physical function of women with VTE was worse at the end of follow‐up compared to women without VTE.

Conclusions

In this prospective cohort, incident VTE was strongly associated with an acute decline in physical function. These results suggest it may be clinically important to consider approaches to ameliorating functional deficits shortly after VTE diagnosis.

     

Genes associated with venous thromboembolism in colorectal cancer patients

Essentials

• The underlying pathophysiological mechanisms behind cancer‐associated thrombosis are unknown.
• We compared expression profiles in tumor cells from patients with and without thrombosis.
• Tumors from patients with thrombosis showed significant differential gene expression profiles.
• Patients with thrombosis had a proinflammatory status and increased fibrin levels in the tumor.

Summary

Background

Venous thromboembolism (VTE) is a frequent complication in patients with cancer, and is associated with significant morbidity and mortality. However, the mechanisms behind cancer‐associated thrombosis are still incompletely understood.

Objectives

To identify novel genes that are associated with VTE in patients with colorectal cancer (CRC).

Methods

Twelve CRC patients with VTE were age‐matched and sex‐matched to 12 CRC patients without VTE. Tumor cells were isolated from surgical samples with laser capture microdissection approaches, and mRNA profiles were measured with next‐generation RNA sequencing.

Results

This approach led to the identification of new genes and pathways that might contribute to VTE in CRC patients. Application of ingenuity pathway analysis indicated significant links with inflammation, the methionine degradation pathway, and increased platelet function, which are all key processes in thrombus formation. Tumor samples of patients with VTE had a proinflammatory status and contained higher levels of fibrin and fibrin degradation products than samples of those without VTE.

Conclusion

This case–control study provides a proof‐of‐principle that tumor gene expression can discriminate between cancer patients with low and high risks of VTE. These findings may help to further unravel the pathogenesis of cancer‐related VTE. The identified genes could potentially be used as candidate biomarkers to select high‐risk CRC patients for thromboprophylaxis.

     

The effect of recanalization on long‐term neurological outcome after cerebral venous thrombosis

Essentials

• The role of cerebral venous thrombosis (CVT) recanalization on neurologic outcome is still debated.
• We studied a large cohort of 508 CVT patients with 419 patient years of radiological follow‐up.
• Recanalization rate is high during the first months after CVT and neurologic outcome is favorable.
• High recanalization grade of CVT independently predicts good neurological outcome.

Summary

Background

Studies with limited sample size and with discordant results described the recanalization time‐course of cerebral venous thrombosis (CVT). The neurological outcome after a first episode of CVT is good, but the role of recanalization on neurological dependence is still debated.

Objectives

The aim of the study is to assess the recanalization rate after cerebral venous thrombosis (CVT) and its prognostic role in long‐term neurological outcome.

Patients/Methods

In a retrospective observational multicenter cohort study, patients with an acute first episode of CVT with at least one available imaging test during follow‐up were enrolled. Patency status of the vessels was categorized as complete, partial or not recanalized. Neurological outcome was defined using the modified Rankin scale (mRS) as good (mRS = 0–1) or poor (mRS = 2–6).

Results

Five‐hundred and eight patients (median [IQR] age, 39 [28.5–49] years; 26% male) were included. Complete or partial recanalization was not differently represented in patients undergoing scans at different periods of time (from 28‐day to 3 month‐period up to a 1–3 year‐period). mRS at the time of follow‐up imaging was available in 483 patients; 92.8% of them had a mRS of 0‐1. CVT recanalization (odds ratio [OR], 2.56; 95% confidence interval [CI], 1.59–4.13) was positively associated, whereas cancer (OR, 0.29; 95% CI, 0.09–0.88), and personal history of venous thromboembolism (VTE) (OR, 0.36; 95% CI, 0.14–0.92) were negatively associated as independent predictors of favorable (mRS = 0–1) outcome at follow‐up.

Conclusions

Most patients with a first CVT had complete or partial recanalization at follow‐up. Recanalization was independently associated with a favorable neurological outcome.

     

Joint effects of prothrombotic genotypes and body height on the risk of venous thromboembolism: the Tromsø study

Essentials

• Body height and prothrombotic genotypes are associated with risk of venous thromboembolism (VTE).
• The joint effect of prothrombotic genotypes and tall stature on VTE risk is scarcely investigated.
• We investigated the joint effect of prothrombotic genotypes and tall stature on VTE risk.
• Prothrombotic genotypes did not yield excess risk of VTE in subjects with a tall stature.

Summary

Background

Studies have reported synergistic effects of prothrombotic single‐nucleotide polymorphisms (SNPs) and obesity on the risk of venous thromboembolism (VTE). Tall stature is associated with an increased VTE risk, but the joint effect of prothrombotic genotypes and tall stature on the VTE risk is unknown.

Aims

To investigate the joint effects of prothrombotic genotypes and tall stature on the VTE risk.

Methods

Cases with incident VTE (n = 676) and a randomly selected age‐weighted subcohort (n = 1842) were sampled from the Tromsø study (cohort follow‐up: 1994–2012). DNA was genotyped for rs6025 (factor V Leiden), rs1799963 (FII), rs8176719 (ABO blood group), rs2066865 (fibrinogen‐γ), and rs2036914 (FIX). Age‐adjusted and sex‐adjusted hazard ratios (HRs) of VTE were calculated by categories of risk alleles (de Haan 5‐SNP score: 0–1, 2–3, and ≥ 4) and body height (< 40th, 40th–80th and > 80th percentiles).

Results

The VTE risk increased by increasing category of body height, and subjects with height ≥ 178 cm had a two‐fold higher VTE risk (HR 2.03; 95% confidence interval [CI] 1.51–2.73) than those with height ≤ 165 cm. The VTE risk also increased across categories of risk alleles. However, the combination of a tall stature and risk alleles, either individual SNPs or risk score, did not result in an excess VTE risk. Subjects with four or more risk alleles and height ≥ 178 cm had a two‐fold (HR 2.08; 95% CI 1.24–3.52) higher VTE risk than subjects ≤ 165 cm with no risk allele or one risk allele.

Conclusions

In contrast to obesity, the presence of prothrombotic genotypes did not result in an excess VTE risk in subjects with a tall stature.     

Age‐adjusted D‐dimer to rule out deep vein thrombosis: findings from the PALLADIO algorithm

Essentials

• The accuracy of the age‐adjusted D‐dimer in suspected venous thromboembolism is still debated.
• We assessed the performance of age‐adjusted D‐dimer combined with the PALLADIO algorithm.
• The age‐adjusted threshold can reduce the need for imaging tests compared to the fixed cut‐off.
• The safety of this approach should be confirmed in large management studies.

Summary

Background

Age‐adjusted D‐dimer has been proposed to increase specificity for the diagnosis of venous thromboembolism (VTE). However, the accuracy of this threshold has been recently questioned.

Objectives

To assess the diagnostic performance of age‐adjusted D‐dimer combined with clinical pretest probability (PTP) in patients with suspected deep vein thrombosis (DVT).

Methods

PALLADIO (NCT01412242) was a multicenter management study that validated a new diagnostic algorithm, incorporating PTP, D‐dimer (using the manufacturer's cut‐off) and limited or extended compression ultrasonography (CUS) in outpatients with clinically suspected DVT. Patients with unlikely PTP and negative D‐dimer had DVT ruled out without further testing (group 1); patients with likely PTP or positive D‐dimer underwent limited CUS (group 2); patients with likely PTP and positive D‐dimer underwent extended CUS (group 3). Patients with DVT ruled out at baseline had a 3‐month follow‐up. In this post‐hoc analysis we evaluated age‐adjusted D‐dimer cut‐off (defined as age times 10 μg L^?1, or age times 5 μg L^?1 for D‐dimers with a lower manufacturer's cut‐off, in patients > 50 years).

Results

In total, 1162 patients were enrolled. At initial visit, DVT was detected in 4.0% of patients in group 2 and 53.0% in group 3. The age‐adjusted D‐dimer, compared with the fixed cut‐off, resulted in 5.1% (95% CI, 4.0–6.5%) reduction of CUS. The incidence of symptomatic VTE during follow‐up was: 0.24% (95% CI, 0.04–1.37) in group 1; 1.12% (95% CI, 0.44–2.85) in group 2; and 1.89% (95% CI, 0.64–5.40) in group 3.

Conclusions

The PALLADIO algorithm using age‐adjusted D‐dimer slightly decreased the number of required imaging tests, but this approach should be confirmed in large management studies.

     

Cancer and risk of cerebral venous thrombosis: a case–control study

Essentials

The risk of cerebral venous thrombosis (CVT) in patients with cancer is not known.

We performed a case‐control study including 594 patients with CVT and 6278 controls.

History of cancer increased the risk of CVT approximately 5‐fold.

The association was strongest with hematological cancer in the first year after diagnosis.

Summary

Background

Cancer is an established risk factor for leg vein thrombosis and pulmonary embolism. Controlled studies assessing the risk of cerebral venous thrombosis (CVT) in patients with cancer have not been performed.

Objective

To assess whether cancer is a risk factor for CVT.

Patients/Methods

This was a case–control study. We assessed consecutive adult patients with CVT from three academic hospitals from 1987 to 2015, and control subjects from the Dutch MEGA study (Multiple Environmental and Genetic Assessment of risk factors for venous thrombosis). We adjusted for age, sex and oral contraceptive use, and stratified for type of cancer and time since diagnosis of cancer.

Results

We included 594 cases and 6278 controls. In total, 53 cases (8.9%) and 160 controls (2.5%) had a history of cancer. Cases were younger (median 42 vs. 48 years), more often female (68% vs. 54%) and more often used oral contraceptives (55% vs. 23%) than controls. The risk of CVT was increased in patients with cancer compared with those without cancer (adjusted odds ratio [aOR], 4.86; 95% confidence interval [CI], 3.46–6.81). Patients with a hematological type of cancer had a higher risk of CVT (aOR, 25.14; 95% CI, 11.64–54.30) than those with a solid type of cancer (aOR, 3.07; 95% CI, 2.03–4.65). The association was strongest in the first year after diagnosis of cancer (hematological aOR, 85.57; 95% CI, 19.70–371.69; solid aOR, 10.50; 95% CI, 5.40–20.42).

Conclusions

Our study indicates that cancer is a strong risk factor for CVT, particularly within the first year of diagnosis and in patients with a hematological type of cancer.     

Reduced‐dose direct oral anticoagulants in the extended treatment of venous thromboembolism: a systematic review and meta‐analysis

Essentials

• In venous thromboembolism (VTE), benefits of extended treatment are balanced by bleeding risks.
• This is a meta‐analysis of reduced‐dose direct oral anticoagulants (DOACs) in extended treatment.
• Reduced‐dose DOACs are as effective as full anticoagulation with bleeding risks similar to placebo.
• Reduced‐dose DOACs are an attractive option for patients in the extended phase of VTE treatment.

Summary

Background

Extended‐duration anticoagulation is beneficial for preventing recurrent venous thromboembolism (VTE). Reduced‐dose direct oral anticoagulants (DOACs) may be preferable if they preserve efficacy and cause less bleeding. We conducted a systematic review and meta‐analysis of trials comparing reduced‐dose DOACs with full‐dose DOACs and aspirin or placebo in the extended phase of VTE treatment.

Methods

A literature search was conducted by use of the MEDLINE, EMBASE and CINAHL databases, supplemented by hand‐searching. One thousand three hundred and ninety‐nine titles were screened, with data from accepted studies being extracted by two independent reviewers. Major outcomes analyzed included recurrent VTE and major and clinically relevant non‐major bleeding events, presented as risk ratios (RRs) and 95% confidence intervals (CI).

Results

Two trials met the prespecified inclusion criteria. Data from 5847 patients were analyzed for efficacy outcomes, and from 5842 patients for safety outcomes. Reduced‐dose DOACs were as effective as full‐dose treatment in preventing recurrent VTE at 1 year (RR 1.12 [95% CI 0.67–1.87]), and more effective than aspirin or placebo (RR 0.26 [95% CI 0.14–0.46]). Rates of major or clinically relevant non‐major bleeding events were similar between patients receiving reduced‐dose DOACs and and those receiving aspirin or placebo (RR 1.19 [95% CI 0.81–1.77]). There was a trend towards less bleeding when reduced‐dose and full‐dose DOACs were compared (RR 0.74 [95% CI 0.52–1.05]).

Conclusions

Extended‐duration treatment of VTE with reduced‐dose DOACs may be as efficacious as full‐dose treatment, with rates of major bleeding being similar to those in patients receiving treatment with aspirin or placebo, but further long‐term studies are needed.

     

Venous thromboembolism in cancer patients receiving neoadjuvant chemotherapy: a systematic review and meta‐analysis

Essentials

• Cancer patients are at risk for venous thromboembolism (VTE).
• The risk of VTE in less advanced stage cancer on neoadjuvant chemotherapy is unclear.
• In over 7800 patients, we found a 7% pooled incidence of VTE during neoadjuvant therapy.
• Highest VTE rates were observed in patients with bladder and esophageal cancer.

Summary

Background

Venous thromboembolism (VTE) is a frequent complication in cancer patients receiving adjuvant treatment. The risk of VTE during neoadjuvant chemo‐radiotherapy remains unclear.

Objectives

This systematic review evaluated the incidence of VTE in patients with cancer receiving neoadjuvant treatment.

Methods

MEDLINE and EMBASE databases were searched from inception to October 2017. Search results were supplemented with screening of conference proceedings of the American Society of Clinical Oncology (2009–2016) and the International Society of Thrombosis and Haemostasis (2003–2016). Two review authors independently screened titles and abstracts, and extracted data onto standardized forms.

Results

Twenty‐eight cohort studies (7827 cancer patients, range 11 to 1398) were included. Twenty‐five had a retrospective design. Eighteen cohorts included patients with gastrointestinal cancer, representing over two‐thirds of the whole study population (n = 6002, 78%). In total, 508 of 7768 patients were diagnosed with at least one VTE during neoadjuvant treatment, for a pooled VTE incidence of 7% (95% CI, 5% to 10%) in the absence of substantial between‐study heterogeneity. Heterogeneity was not explained by site of cancer or study design characteristics. VTE presented as pulmonary embolism in 22% to 96% of cases (16 cohorts), and it was symptomatic in 22% to 100% of patients (11 cohorts). The highest VTE rates were observed in patients with bladder (10.6%) or esophageal (8.4%) cancer.

Conclusions

This review found a relatively high incidence of VTE in cancer patients receiving neoadjuvant therapy in the presence of some between‐study variation, which deserves further evaluation in prospective studies.