Inflammation markers and their trajectories after deep vein thrombosis in relation to risk of post-thrombotic syndrome.

BACKGROUND: Post-thrombotic syndrome (PTS) is a frequent chronic complication of deep vein thrombosis (DVT). OBJECTIVE: In the BioSOX study, we investigated whether inflammation markers predict the risk of PTS after DVT. METHODS: We measured C-reactive protein (CRP), ICAM-1, interleukin (IL)-6, and IL-10, at baseline, and 1 month and 6 months after a first proximal DVT, among 803 participants in the SOX trial. Participants were prospectively followed for 24 months for development of PTS. RESULTS: Median CRP levels at 1 month, ICAM-1 levels at baseline, 1 month and 6 months, IL-6 levels at 1 month and 6 months and IL-10 levels at 6 months were higher in patients who developed PTS than in those who did not. Multivariable regression with the median as a cutoff showed risk ratios (RRs) for PTS of 1.23 (95% confidence interval [CI] 1.05-1.45) and 1.25 (95% CI 1.05-1.48) for ICAM-1 at 1 month and 6 months, respectively, and 1.27 (95% CI 1.07-1.51) for IL-10 at 6 months. Quartile-based analysis demonstrated a dose-response association between ICAM-1 and PTS. ICAM-1 and IL-10 were also associated with PTS severity. Analysis of biomarker trajectories after DVT demonstrated an association between the highest-trajectory group of ICAM-1 and PTS. CONCLUSIONS: In this prospective study, ICAM-1 over time was most consistently associated with the risk of PTS. Further study is required to confirm these findings and assess their potential clinical relevance.

Graduated compression stockings to treat acute leg pain associated with proximal DVT. A randomised controlled trial.

Acute deep venous thrombosis (DVT) causes leg pain. Elastic compression stockings (ECS) have potential to relieve DVT-related leg pain by diminishing the diameter of distended veins and increasing venous blood flow. It was our objective to determine whether ECS reduce leg pain in patients with acute DVT. We performed a secondary analysis of the SOX Trial, a multicentre randomised placebo controlled trial of active ECS versus placebo ECS to prevent the post-thrombotic syndrome.The study was performed in 24 hospital centres in Canada and the U.S. and included 803 patients with a first episode of acute proximal DVT. Patients were randomised to receive active ECS (knee length, 30-40 mm Hg graduated pressure) or placebo ECS (manufactured to look identical to active ECS, but lacking therapeutic compression). Study outcome was leg pain severity assessed on an 11-point numerical pain rating scale (0, no pain; 10, worst possible pain) at baseline, 14, 30 and 60 days after randomisation. Mean age was 55 years and 60% were male. In active ECS patients (n=409), mean (SD) pain severity at baseline and at 60 days were 5.18 (3.29) and 1.39 (2.19), respectively, and in placebo ECS patients (n=394) were 5.38 (3.29) and 1.13 (1.86), respectively. There were no significant differences in pain scores between groups at any assessment point, and no evidence for subgroup interaction by age, sex or anatomical extent of DVT. Results were similar in an analysis restricted to patients who reported wearing stockings every day. In conclusion, ECS do not reduce leg pain in patients with acute proximal DVT.

Is thrombophilia associated with placenta-mediated pregnancy complications? A prospective cohort study.

BACKGROUND: Case control studies suggest that genetic thrombophilias increase the risk of placenta-mediated pregnancy complications (pregnancy loss, small for gestational age (SGA), preeclampsia and/or placental abruption). Cohort studies have not supported this association but were underpowered to detect small effects. OBJECTIVE: To determine if factor V Leiden (FVL) or the prothrombin gene mutation (PGM) were associated with placenta-mediated pregnancy complications. PATIENTS/METHODS: A prospective cohort of unselected, consenting pregnant women at three Canadian tertiary care hospitals had blood drawn in the early second trimester and were genotyped for FVL and PGM after delivery. The main outcome measure was a composite of pregnancy loss, SGA < 10th percentile, preeclampsia or placental abruption. RESULTS: Complete primary outcome and genetic data were available for 7343 women. Most were Caucasian (77.7%, n = 5707), mean age was 30.4 (± 5.1) years, and half were nulliparous. There were 507 (6.9%) women with FVL and/or PGM; 11.64% had a placenta-mediated pregnancy complication. Of the remaining 6836 women, 11.23% experienced a complication. FVL and/or PGM was associated with a relative risk of 1.04 (95% CI, 0.81-1.33) for the composite outcome, with similar results after adjustment for important covariates. CONCLUSIONS: Carriers of FVL or PGM are not at significantly increased risk of these pregnancy complications.

Major bleeding during secondary prevention of venous thromboembolism in patients who have completed anticoagulation: a systematic review and meta-analysis.

BACKGROUND: The risk of major bleeding in patients who have completed anticoagulation therapy for unprovoked venous thromboembolism (VTE) is unknown. OBJECTIVE: To report the major bleeding and fatal bleeding rates in patients randomized to placebo or observation (i.e. no anticoagulation therapy) for the secondary prevention of recurrent VTE. PATIENTS AND METHODS: We performed a systematic review and meta-analysis of the literature to summarize the rates of major bleeding and fatal bleeding in patients randomized to placebo or observation during the secondary prevention of VTE. Unrestricted searches of MEDLINE (January 1, 1950 to August 31, 2013), Embase (January 1, 1980 to August 31, 2013), and the Cochrane Register of Controlled Trials using the OVID interface were conducted. Publications from potentially relevant journals were also searched by hand. We used a random-effects model to pool study results and I(2) testing to assess for heterogeneity. RESULTS: The analysis included 11 studies and 3965 patients who were followed for a median of 24 months. The overall pooled major bleeding rate was 0.45 per 100 patient-years (95% CI 0.29-0.64, I(2) = 0%), and the overall pooled fatal bleeding rate was 0.14 per 100 patient-years (95% CI 0.057-0.26, I(2) = 0%). CONCLUSIONS: Patients not receiving anticoagulant therapy for the secondary prevention of VTE experience major bleeding events, and this may have an impact on recommendations for extended treatment in this patient population.

Predictors of post-thrombotic syndrome in a population with a first deep vein thrombosis and no primary venous insufficiency.

BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent complication of deep vein thrombosis (DVT). Its diagnosis is based on clinical characteristics. However, symptoms and signs of PTS are non-specific, and could result from concomitant primary venous insufficiency (PVI) rather than DVT. This could bias evaluation of PTS. METHODS: Using data from the REVERSE multicenter study, we assessed risk factors for PTS in patients with a first unprovoked unilateral proximal DVT 5-7 months earlier who were free of clinically significant PVI (defined as absence of moderate or severe venous ectasia in the contralateral leg). RESULTS: Among the 328 patients considered, the prevalence of PTS was 27.1%. Obesity (odds ratio [OR] 2.6 [95% confidence interval (CI) 1.5-4.7]), mild contralateral venous ectasia (OR 2.2 [95% CI 1.1-4.3]), poor International Normalized Ratio (INR) control (OR per additional 1% of time with INR < 2 during anticoagulant treatment of 1.018 [95% CI 1.003-1.034]) and the presence of residual venous obstruction on ultrasound (OR 2.1 [95% CI 1.1-3.7]) significantly increased the risk for PTS in multivariable analyses. When we restricted our analysis to patients without any signs, even mild, of contralateral venous insufficiency (n = 244), the prevalence of PTS decreased slightly to 24.6%. Only obesity remained an independent predictor of PTS (OR 2.6 [95% CI 1.3-5.0]). Poor INR control and residual venous obstruction also increased the risk, but the results were no longer statistically significant (OR 1.017 [95% CI 0.999-1.035] and OR 1.7 [95% CI 0.9-3.3], respectively). CONCLUSIONS: After a first unprovoked proximal DVT, obese patients and patients with even mild PVI constitute a group at increased risk of developing PTS for whom particular attention should be paid with respect to PTS prevention. Careful monitoring of anticoagulant treatment may prevent PTS.

Risk of post-thrombotic syndrome after subtherapeutic warfarin anticoagulation for a first unprovoked deep vein thrombosis: results from the REVERSE study.

BACKGROUND: Risk factors for post-thrombotic syndrome (PTS) remain poorly understood. OBJECTIVES: In this multinational multicenter study, we evaluated whether subtherapeutic warfarin anticoagulation was associated with the development of PTS. METHODS: Patients with a first unprovoked deep venous thrombosis (DVT) received standard anticoagulation for 5-7 months and were then assessed for PTS. The time in the therapeutic range was calculated from the international normalized ratio (INR) data. An INR below 2, more than 20% of the time, was considered as subtherapeutic anticoagulation. RESULTS: Of the 349 patients enrolled, 97 (28%) developed PTS. The overall frequency of PTS in patients with subtherapeutic anticoagulation was 33.5%, compared with 21.6% in those with an INR below two for ≤ 20% of the time (P = 0.01). During the first 3 months of therapy, the odds ratio (OR) for developing PTS if a patient had subtherapeutic anticoagulation was 1.78 (95% confidence interval [CI] 1.10-2.87). After adjusting for confounding variables, the OR was 1.84 (95% CI 1.13-3.01). Corresponding ORs for the full period of anticoagulation were 1.83 (95% CI 1.14-3.00) [crude] and 1.88 (95% CI 1.15-3.07) [adjusted]. CONCLUSION: Subtherapeutic warfarin anticoagulation after a first unprovoked DVT was significantly associated with the development of PTS.

Comparison of the Villalta post-thrombotic syndrome score in the ipsilateral vs. contralateral leg after a first unprovoked deep vein thrombosis.

BACKGROUND: Post-thrombotic syndrome (PTS) is the most frequent complication of a deep vein thrombosis (DVT). International guidelines recommend assessing PTS with the Villalta scale, a clinical measure that incorporates venous symptoms and signs in the leg ipsilateral to a DVT. However, these signs and symptoms are not specific for PTS and their prevalence and relevance in the contralateral leg have not previously been studied. METHODS: Using data from the REVERSE prospective multicentre cohort study, we compared the Villalta total score and prevalence of venous signs and symptoms in the ipsilateral vs. contralateral leg in patients with a first, unilateral DVT 5 to 7 months previously. RESULTS: Among the 367 patients analyzed, the mean Villalta score was higher in the ipsilateral than in the contralateral leg (mean ± standard deviation [SD] 3.7 [3.4] vs. 1.9 [2.5], respectively; P<0.0001). Villalta scores in the ipsilateral and contralateral legs were strongly correlated (r=0.68; P<0.0001). Ipsilateral PTS (defined by a Villalta total score >4) was present in 31.6% (n=116) of patients. Among these, 39.7% (n=46) of patients had a Villalta score >4 in the contralateral leg, and the distribution of Villalta symptoms and signs components was similar between the legs. CONCLUSIONS: Villalta scores in the ipsilateral and contralateral legs are strongly correlated. Almost half of cases considered to be PTS might reflect pre-existing symptomatic chronic venous disease. Alternatively, patients with pre-existing chronic venous disease might be more prone to developing PTS after a DVT. Performing a bilateral assessment of Villalta scores at the acute phase of DVT could be of clinical interest from a diagnostic, prognostic and therapeutic point of view.

Baseline imaging after therapy for unprovoked venous thromboembolism: a randomized controlled comparison of baseline imaging for diagnosis of suspected recurrence.

BACKGROUND: After a first unprovoked venous thromboembolism (VTE), many patients have residual pulmonary and/or lower limb vascular obstruction following completion of short-term anticoagulation. Residual vascular obstruction may complicate the diagnosis of recurrent VTE. Whether baseline imaging, conducted after completion of anticoagulation, helps in interpreting diagnostic testing in patients who subsequently have suspected recurrent VTE is unknown. STUDY DESIGN: The REVERSE study is a cohort study whose primary aim was to derive a clinical decision rule to guide the duration of anticoagulation after a first unprovoked VTE. All patients underwent baseline imaging after completing 5-7 months of anticoagulant therapy. We performed a post hoc randomized controlled comparison among 121 patients investigated for a suspected recurrent VTE during follow-up: the decision on recurrent VTE with or without baseline imaging was made available to two independent adjudicators. RESULTS: The proportion of patients not classifiable for recurrent VTE was statistically significantly higher in the group with no baseline imaging than in the group with baseline imaging: one in five as compared with one in 25. The interobserver agreement between the two adjudicators was better in the group with baseline imaging than in the group with no baseline imaging: κ-values were 0.78 and 0.54, respectively. CONCLUSIONS: In patients with a first unprovoked VTE, baseline imaging at completion of anticoagulant therapy helps in interpreting diagnostic tests performed in cases of suspected recurrent VTE.

Residual vein obstruction to predict the risk of recurrent venous thromboembolism in patients with deep vein thrombosis: a systematic review and meta-analysis.

BACKGROUND: Residual vein obstruction (RVO) detected on compression ultrasonography of the leg after a few months of anticoagulation therapy might be able to identify patients with deep vein thrombosis (DVT) at high risk of having a recurrent venous thromboembolism (VTE). AIM: To determine whether RVO is associated with an increased risk of recurrent events in patients with DVT. PATIENTS AND METHODS: A systematic literature search strategy was conducted using MEDLINE, EMBASE, and the Cochrane Register of Controlled Trials. We selected 14 articles (nine prospective cohort studies and five randomized controlled trials) that included patients with DVT who had an assessment for RVO with the use of compression ultrasonography. Two reviewers independently extracted data onto standardized forms. RESULTS: Overall, the presence of RVO was not associated with an increased risk of recurrent VTE (odds ratio [OR] 1.24, 95% confidence interval [CI] 0.9-1.7) in patients with unprovoked DVT who stopped oral anticoagulation therapy at the time of RVO assessment. However, RVO was significantly associated with recurrent VTE in patients with any (unprovoked or provoked) DVT (OR 1.5, 95% CI 1.1-2.0). CONCLUSIONS: RVO was associated with a modestly increased risk of recurrent VTE in patients with DVT (unprovoked and provoked). However, RVO did not seem to be a predictor of recurrent VTE in patients with unprovoked DVT following anticoagulation discontinuation. Further prospective studies are needed to assess the role of RVO in patients with unprovoked DVT.

Serum lipoprotein (a) levels in patients with first unprovoked venous thromboembolism is not associated with subsequent risk of recurrent VTE.

INTRODUCTION: Case-control studies suggest that elevated lipoprotein (a) (Lp(a)) is a risk factor for first venous thromboembolism (VTE). Lp(a) has not been prospectively investigated as a possible risk factor for recurrent VTE in first unprovoked VTE patients. We sought to determine if serum Lp(a) levels in patients with unprovoked VTE who discontinue anticoagulants after 5 to 7 months of therapy predict VTE recurrence in a prospective cohort study. MATERIALS AND METHODS: Serum Lp(a) measurements were obtained from 510 first unprovoked VTE patients treated for 5 -7 months with anticoagulants in a 12 center study. Patients were subsequently followed for a mean of 16.9 months (SD+/-11.2) for symptomatic VTE recurrence which was independently adjudicated with reference to baseline imaging. RESULTS: There was no significant association between Lp(a) as a continuous variable and recurrent VTE nor in gender stratified subgroups. No statistically significant differences were observed in the median Lp(a) concentrations between patients who recurred and those who did not recur (median (interquartile range): 0.09 g/L (0.17) versus 0.06 g/L (0.11) respectively; p=0.15). The Lp(a) cut-off point of 0.3g/L was not significantly associated with recurrent VTE for the overall population nor in gender stratified subgroups. CONCLUSIONS: Elevated serum Lp(a) does not appear to be associated with recurrent VTE in patients with history of first unprovoked VTE and may not play a role in identifying patients with unprovoked VTE at high risk of recurrence. There was no optimal predictive threshold for the overall population or for sex sub-groups and Lp(a)>or=0.3 g/L was not a significant predictor of recurrent VTE.

Patients with a first symptomatic unprovoked deep vein thrombosis are at higher risk of recurrent venous thromboembolism than patients with a first unprovoked pulmonary embolism.

BACKGROUND: Previous studies are mixed as to whether patients with unprovoked pulmonary embolism (PE) have a higher rate of venous thromboembolism (VTE) recurrence after anticoagulation is discontinued than patients with unprovoked deep vein thrombosis (DVT). OBJECTIVES: To determine whether patients with unprovoked PE have a higher rate of VTE recurrence than patients with unprovoked DVT in a prospective multicenter cohort study. PATIENTS/METHODS: Six hundred and forty-six patients with a first episode of symptomatic unprovoked VTE were treated with heparin and subsequent oral anticoagulation for 5-7 months, and were followed every 6 months for recurrent VTE after their anticoagulant therapy was discontinued. RESULTS: Of 646 patients, 194 had isolated PE, 339 had isolated DVT, and 113 had both DVT and PE. After a mean of 18 months of follow-up, there were 91 recurrent VTE events (9.5% annualized risk of recurrent VTE in the total population). The crude recurrent VTE rate for the isolated PE, isolated DVT and DVT and PE groups were 7.7%, 16.5% and 17.7%, respectively. The relative risk of recurrent VTE for isolated DVT vs. isolated PE was 2.1 (95% confidence interval 1.2-3.7). CONCLUSIONS: This study has demonstrated that patients with a first episode of unprovoked isolated DVT are 2.1 times more likely to have a recurrent VTE episode than patients with a first episode of unprovoked isolated PE. These findings need to be considered when determining the optimal duration of anticoagulant therapy for patients with unprovoked VTE.

Subsegmental pulmonary embolism diagnosed by computed tomography: incidence and clinical implications. A systematic review and meta-analysis of the management outcome studies.

BACKGROUND: Multiple-detectors computed tomographic pulmonary angiography (CTPA) has a higher sensitivity for pulmonary embolism (PE) within the subsegmental pulmonary arteries as compared with single-detector CTPA. Multiple-detectors CTPA might increase the rate of subsegmental PE diagnosis. The clinical significance of subsegmental PE is unknown. We sought to summarize the proportion of subsegmental PE diagnosed with single- and multiple-detectors CTPA and assess the safety of diagnostic strategies based on single- or multiple-detectors CTPA to exclude PE. PATIENTS AND METHODS: A systematic literature search strategy was conducted using MEDLINE, EMBASE and the Cochrane Register of Controlled Trials. We selected 22 articles (20 prospective cohort studies and two randomized controlled trials) that included patients with suspected PE who underwent a CTPA and reported the rate of subsegmental PE. Two reviewers independently extracted data onto standardized forms. RESULTS: The rate of subsegmental PE diagnosis was 4.7% [95% confidence interval (CI): 2.5-7.6] and 9.4 (95% CI: 5.5-14.2) in patients that underwent a single- and multiple-detectors CTPA, respectively. The 3-month thromboembolic risks in patients with suspected PE and who were left untreated based on a diagnostic algorithm including a negative CTPA was 0.9% (95% CI: 0.4-1.4) and 1.1% (95% CI: 0.7-1.4) for single- and multiple-detectors CTPA, respectively. CONCLUSION: Multiple-detectors CTPA seems to increase the proportion of patients diagnosed with subsegmental PE without lowering the 3-month risk of thromboembolism suggesting that subsegmental PE may not be clinically relevant.

Safety of excluding acute pulmonary embolism based on an unlikely clinical probability by the Wells rule and normal D-dimer concentration: a meta-analysis.

INTRODUCTION: The Wells clinical decision rule (CDR) and D-dimer tests can be used to exclude pulmonary embolism (PE). We performed a meta-analysis to determine the negative predictive value (NPV) of an "unlikely" CDR (

Increased mortality in hemodialysis patients having specific antibodies to the platelet factor 4-heparin complex.

Heparin-induced thrombocytopenia is a serious complication of heparin therapy that can lead to thromboembolism, cardiovascular events, and death. Hemodialysis patients are repeatedly exposed to heparin and are at risk for developing antibodies to the platelet factor 4-heparin (PF4-H) complex. We sought to determine the association between PF4-H antibodies and mortality in a prospective cohort of 419 asymptomatic hemodialysis patients. Pre-dialysis blood samples were screened for nonspecific PF4-H antibodies, and all positive and indeterminate samples were subsequently tested using immunoglobulin (Ig)G-specific PF4-H and platelet serotonin-release assays. During a median follow-up of 2.5 years there were 129 all-cause deaths. After controlling for potential confounding variables, the relative risk of death was significantly increased for patients with IgG-specific PF4-H antibodies and further elevated with an indeterminate serotonin-release assay. Our study suggests that IgG-specific PF4-H antibody formation is associated with increased mortality in hemodialysis patients.