Alessandro Squizzato

Diagnostic accuracy of D-dimer test for exclusion of venous thromboembolism: a systematic review

Summary.  Background: The reported diagnostic accuracy of the D‐dimer test for exclusion of deep vein thrombosis (DVT) and pulmonary embolism (PE) varies. It is unknown to what extent this is due to differences in study design or patient groups, or to genuine differences between D‐dimer assays. Methods: Studies evaluating the diagnostic accuracy of the D‐dimer test in the diagnosis of venous thromboembolism were systematically searched for in the MEDLINE and EMBASE databases up to March 2005. Reference lists of all included studies and of reviews related to the topic of the present meta‐analysis were manually searched for other additional potentially eligible studies. Two reviewers independently extracted study characteristics using standardized forms. Results: In total, 217 D‐dimer test evaluations for DVT and 111 for PE were analyzed. Several study design characteristics were associated with systematic differences in diagnostic accuracy. After adjustment for these features, the sensitivities of the D‐dimer enzyme‐linked immunofluorescence assay (ELFA) (DVT 96%; PE 97%), microplate enzyme‐linked immunosorbent assay (ELISA) (DVT 94%; PE 95%), and latex quantitative assay (DVT 93%; PE 95%) were superior to those of the whole‐blood D‐dimer assay (DVT 83%; PE 87%), latex semiquantitative assay (DVT 85%; PE 88%) and latex qualitative assay (DVT 69%; PE 75%). The latex qualitative and whole‐blood D‐dimer assays had the highest specificities (DVT 99%, 71%; PE 99%, 69%). Conclusions: Compared to other D‐dimer assays, the ELFA, microplate ELISA and latex quantitative assays have higher sensitivity but lower specificity, resulting in a more confident exclusion of the disease at the expense of more additional imaging testing. These conclusions are based on the most up‐to‐date and extensive systematic review of the topic area, including 184 articles, with 328 D‐dimer test evaluations.

Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists

Prothrombin complex concentrates (PCCs) are recommended as the treatment of choice in warfarin-related coagulopathy. However, the risk of thromboembolic complications associated with their use is not well defined. We performed a meta-analysis to estimate the rate of thromboembolic complications in patients receiving vitamin K antagonists (VKAs) treated with PCCs for bleeding or before urgent surgery. Medline and Embase databases were searched. Two reviewers performed study selection and extracted data independently. Studies providing data on incidence of thromboembolic complications in VKA-treated patients were eligible for the study. Weighted mean proportion of the rate of thromboembolic complications and the mortality rate were calculated. Twenty-seven studies (1,032 patients) were included. Seven studies used 3-factor, and 20 4-factor PCCs. Twelve patients had a thromboembolic complication (weighted mean 1.4%; 95% CI 0.8-2.1), of which two were fatal. The incidence of thromboembolic events was 1.8% (95% CI 1.0-3.0) in patients treated with 4-factor PCCs, and 0.7% (95% CI 0.0-2.4) in patients treated with 3-factor PCCs. Total mortality rate was 10.6% (95% CI 5.9-16.6). In conclusion, our results suggest there is a low but quantifiable risk of thromboembolism in VKA-treated patients receiving PCCs for anticoagulation reversal. These findings should be confirmed in randomised, controlled trials.

Thyroid Diseases and Cerebrovascular Disease

Background and Purpose— Acute cerebral ischemia has been described in different diseases of the thyroid gland, and not only as a result of thyrotoxic atrial fibrillation and cardioembolic stroke. The purpose of this review is to summarize the studies on the relationship between thyroid diseases and cerebrovascular diseases, discussing the main findings for overt hyperthyroidism and hypothyroidism, as well as for subclinical thyroid dysfunction. Summary of Review— In overt hyperthyroidism, cardioembolic stroke is clearly associated to thyrotoxic atrial fibrillation, and in subclinical hyperthyroidism with serum thyroid-stimulating hormone levels <0.1 mU/L, the incidence of atrial fibrillation is increased. Although in vitro and in vivo studies indicate a hypercoagulability state in hyperthyroidism, there is insufficient evidence to prove that this state leads to an increased risk of cardiac emboli. However, the hypothesis that overt hyperthyroidism may cause acute cerebral venous thrombosis is intriguing. Possible associations between hyperthyroidism and Moyamoya or Giant cell arteritis have only been described in case reports. There is enough evidence that overt hypothyroidism is associated with several traditional and newer atherosclerotic risk factors, especially hypertension, hyperlipidemia, and hyperhomocysteinemia. For subclinical hypothyroidism, these associations are less certain. Hypothyroidism has been associated with signs of aortic or coronary atherosclerosis, but no case-control or cohort studies have ever investigated hypothyroidism as a possible risk factor for atherothrombotic stroke. Conclusions— Hyperthyroidism is associated with atrial fibrillation and cardioembolic stroke. Hypothyroidism is associated with a worse cardiovascular risk factor profile and leads to progression of atherosclerosis. Associations between hyperthyroidism and acute cerebral venous thrombosis, Moyamoya, and Giant cell arteritis have been suggested, but sound evidence is lacking. Additional studies are needed to clarify these issues.

Hypercoagulable State in Cushing's Syndrome: A Systematic Review

CONTEXT It has been debated whether an increased risk of venous thromboembolism (VTE) exists in patients with Cushings syndrome. OBJECTIVE We aimed to summarize published literature on the effects of endogenous hypercortisolism on coagulation and fibrinolysis, as well as on the clinical outcome of VTE. DATA SOURCES We searched the MEDLINE and EMBASE databases up to July 2008. Review of reference lists further identified candidate studies. STUDY SELECTION Two investigators independently performed study selection and data extraction. Eligible studies had to include Cushings syndrome patients and either evaluate hemostatic parameters in comparison with control persons or posttreatment levels or describe the occurrence of VTE. DATA EXTRACTION The Newcastle-Ottawa Scale was used to assess study quality. A scoring system divided studies into categories of low, medium and high quality. DATA SYNTHESIS Of 441 identified publications, 15 reports were included. They contained information on eight cross-sectionals, two intervention, and eight cohort studies. No high-quality studies were identified. Hypercoagulability was suggested by high levels of factor VIII, factor IX, and von Willebrand factor and by evidence of enhanced thrombin generation. A risk of 1.9 and 2.5% was reported for VTE not provoked by surgery, whereas risk of postoperative VTE varied between 0 and 5.6%, with one outlier of 20%. VTE was reported as the cause of death in 0-1.9% of Cushings syndrome patients. CONCLUSIONS Available studies suggest a high risk of venous thrombosis in patients with Cushings syndrome. Glucocorticoid-induced hypercoagulability as well as surgery and obesity almost certainly contribute to this thrombotic tendency.

Prevalence and Clinical History of Incidental, Asymptomatic Pulmonary Embolism: A Meta-Analysis

CONTEXT Recently, there has been an increasing number of reports of incidental pulmonary embolism (PE) in patients undergoing chest computer tomography (CT) for reasons other than the research of suspected PE. Natural history of incidental PE remains unclear. OBJECTIVES To estimate the prevalence of incidental PE, to assess potential factors associated with incidental PE, and to evaluated its clinical history. DATA SOURCES MEDLINE, EMBASE databases (up to January 2009). STUDY SELECTION Studies were included if the prevalence of incidental PE was assessed using CT scanning. DATA EXTRACTION The prevalence of incidental PE in these patients was documented. Separate data for inpatients and outpatients and according to the reason for CT scanning were collected. Weighted mean proportion of the prevalence of incidental PE was calculated. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to test the association with potential predictors of incidental PE. RESULTS Twelve studies for a total of more than 10 thousand patients were included. The weighted mean prevalence of incidental PE was 2.6% (95% CI 1.9, 3.4). Hospitalization at the time of CT scanning and the presence of cancer were associated with a significantly increased risk of incidental PE (OR 4.27 and OR 1.80 respectively). CONCLUSIONS The prevalence of incidental PE is clinically relevant. Future studies are necessary to properly evaluate the clinical history of these patients.

JAK2V617F mutation for the early diagnosis of Ph- myeloproliferative neoplasms in patients with venous thromboembolism: a meta-analysis.

Recent studies suggested that JAK2V617F mutation is frequent in patients with splanchnic vein thrombosis (SVT) but not in patients with other venous thromboembolic events (VTE). However, whether screening for the JAK2V617F mutation in VTE patients is justified remains unclear. Therefore, we performed a systematic review to assess the frequency of JAK2 mutation in VTE patients and the role of JAK2V617F mutation in the diagnosis of myeloproliferative neoplasms. MEDLINE and EMBASE databases were searched. Two reviewers independently performed study selection and extracted study characteristics. Pooled odds ratios of case-control studies and weighted mean proportion of the prevalence of JAK2V617F mutation of uncontrolled series were calculated. Twenty-four studies involving 3123 patients were included. Mean prevalence of JAK2 mutation was 32.7% (95% confidence interval, 25.5%-35.9%) in SVT patients. JAK2 mutation was associated with increased risk of SVT (odds ratio, 53.98; 95% confidence interval, 13.10-222.45). Mean prevalence of JAK2 mutation in other VTE patients was low (range, 0.88%-2.57%). Presence of JAK2V617F mutation in SVT patients was associated with a subsequent diagnosis of myeloproliferative neoplasm in many patients. JAK2 mutation is strongly associated with SVT, and routine screening of JAK2 mutation appears to be indicated in these patients.

Neutrophils and clinical outcomes in patients with acute coronary syndromes and/or cardiac revascularisation. A systematic review on more than 34,000 subjects.

Some studies have suggested that high levels of total white blood cell (WBC) count and C-reactive protein (CRP) may be considered as independent prognostic factors in patients with acute coronary syndromes (ACS) and/or after cardiac revascularisation by percutaneous coronary intervention or coronary artery bypass grafting surgery. Evidence on the role of neutrophils in cardiovascular disease is less compelling. Therefore, we conducted a systematic review of the literature with the aim of identifying all the available evidence to clarify the role of neutrophils (absolute or relative count, neutrophil/lymphocyte ratio) as a prognostic risk factor in patients with ACS and/or cardiac revascularisation. All published studies evaluating the role of neutrophils as a risk factor for clinical outcomes were assessed using the MEDLINE and EMBASE databases. Study selection, data extraction and validity assessment was performed independently by two reviewers. Twenty-one studies (17 of which had positive results) for a total of more than 34,000 patients were included. Ten of 13 studies in ACS patients found that neutrophils measured on-admission are related to mortality rate and/or to major adverse clinical events. A predictive value of neutrophils after cardiac revascularisation procedures was reported in seven out of eight studies. Most of the studies showed that neutrophils were independent predictors of cardiovascular outcomes when analysed concomitantly with other markers of inflammation (WBC, CRP). The findings of our systematic review highlight the potential application of this inexpensive and readily available inflammatory marker for risk stratification in patients with ACS and/or cardiac revascularisation.

Incidence of chronic pulmonary hypertension in patients with previous pulmonary embolism

INTRODUCTION The true incidence of chronic thromboembolic pulmonary hypertension (CTPH) remains a matter of debate. Symptomatic CTPH is probably more common than previously reported, whereas the occurrence of asymptomatic CTPH has not been defined since very limited evidence on the incidence of asymptomatic CTPH diagnosed with echocardiography Doppler are currently available. We therefore carried out a prospective cohort study to assess the incidence of CTPH diagnosed with echocardiography Doppler in consecutive patients with a first episode of PE. METHODS Consecutive patients with a first episode of PE were evaluated with Doppler transthoracic echocardiography within 6 to 12 months after the index event. Pulmonary hypertension was defined as a systolic pulmonary artery pressure > or =40 mmHg at rest in the presence of residual perfusion defects at perfusion scintigraphy. Presence of symptoms related to pulmonary hypertension was evaluated with a standardized questionnaire. RESULTS Ninety-one patients (mean age 61.9+/-15.7 years; range 22-89; 39 men) were enrolled. Eight patients (8.8%; 95% CI 4.5,16.4) had CTPH: of these, 4 (4.4%; 95% CI 2.0, 9.3) were symptomatic. CONCLUSIONS Asymptomatic CTPH is not an uncommon finding after PE. Larger prospective trials with a longer follow up should assess the prognostic significance of asymptomatic CPTH.

Systematic review on the effect of glucocorticoid use on procoagulant, anti-coagulant and fibrinolytic factors.

Summary.  Background: Whether glucocorticoid use contributes to a hypercoagulable state, and thereby enhances the thrombotic risk, is controversial. Objective: We aimed to examine the effects of glucocorticoid use on coagulation and fibrinolysis. Methods: MEDLINE and EMBASE databases were searched to identify published studies comparing glucocorticoid treatment with a glucocorticoid‐free control situation. Subjects could be either patients or healthy volunteers. Two investigators independently performed study selection and data extraction. Results were expressed as standardized mean difference, if possible; data were pooled with a random‐effects model. Results: Of the 1967 identified publications, 36 papers were included. In healthy volunteers, a clear rise in factor (F)VII, VIII and XI activity was observed after glucocorticoid treatment, but these data alone provided insufficient evidence to support hypercoagulability. However, during active inflammation, glucocorticoids significantly increased levels of plasminogen activator inhibitor‐1 (PAI‐1), whereas levels of von Willebrand factor (VWF) and fibrinogen decreased. Peri‐operative use of glucocorticoids inhibited the increase in tissue‐type plasminogen activator induced by surgery. Conclusions: The present study showed differential effects of glucocorticoids depending on the clinical situation in which it is given, most likely as a result of their disease modifying properties. Clinical outcome studies are needed to adequately assess the risk‐benefit of glucocorticoid use per population when thrombotic complication is the focus.

Statins, fibrates, and venous thromboembolism: a meta-analysis.

AIMS The aim is to make a systematic review of the literature to assess the effect of lipid-lowering drugs on venous thromboembolism (VTE) occurrence. METHODS AND RESULTS MEDLINE and EMBASE databases were searched to identify studies that evaluated the effect of lipid-lowering drugs, in particular statins and fibrates, on VTE risk until April 2009. A scoring system was used to divide studies into two quality categories. Odds ratios (ORs) and 95% confidence intervals (CIs) were then calculated and pooled using a fixed and a random-effects model. Statistical heterogeneity was evaluated through the use of I(2) statistics. Three randomized controlled trials (RCTs), three cohort, and eight case-control studies were included in our systematic review, for a total of 863 805 patients. Statins use significantly reduced VTE risk [OR, 0.81; 95% CI, 0.66-0.99, random-effect model)]. There was a very high heterogeneity among the studies (I(2) > 80%). The use of fibrates was associated with a significant increase in the risk of VTE (OR, 1.58; 95% CI, 1.23-2.02), without heterogeneity (I(2) = 0%). Data on other lipid-lowering drugs were lacking. CONCLUSION This meta-analysis of available literature suggests that statins may lower the risk of VTE, whereas fibrates may increase this risk. Due to several methodological limitations, this conclusion should be considered with caution, and additional, specifically designed RCTs are warranted.