Optimal long-term anticoagulation after acute pulmonary embolism: current state of the art and a look into the near future.

PURPOSE OF REVIEW: This review aims to summarize the current state of the art and future directions in optimal long-term anticoagulation following acute pulmonary embolism (PE). RECENT FINDINGS: Actual studies and guidelines underscore the preference for direct oral anticoagulants (DOAC) in standard therapeutic doses for maintenance therapy post-PE, while considering patient-specific factors and dose-reduction criteria. Risk stratification should always include the assessment of concomitant trigger- or risk factors regarding their strength and persistence. The use of tools like specific scores can facilitate the identification of optimal candidates for long-term therapy, emphasizing once more personalized approaches and strategies. Special patient groups, such as cancer associated thrombosis, chronic thromboembolic pulmonary hypertension or antiphospholipid syndrome require even more tailored therapy approaches. SUMMARY: Optimal long-term anticoagulation post-PE should be guided by straightforward and individual risk assessment strategies. The array of indications for DOACs has gotten wider in last years, also within special patient groups. Still, chronic thromboembolic pulmonary hypertension and antiphospholipid syndrome remains domain of vitamin K agonists.

Soluble urokinase plasminogen activator receptor (suPAR) in bronchoalveolar fluid and blood in critically ill patients-a prospective cohort study.

INTRODUCTION: Soluble urokinase plasminogen activator receptor (suPAR) is a biologically active protein and increased levels are associated with worse outcomes in critically ill patients. suPAR in bronchoalveolar fluid (BALF) may be helpful to differentiate between types of acute respiratory distress syndrome (ARDS) and may have potential for early detection of fungal infection. METHODS: We prospectively investigated levels of suPAR in BALF and serum in critically ill patients who underwent bronchoscopy for any reason at the ICU of the Department of Internal Medicine, Medical University of Graz, Graz, Austria. RESULTS: Seventy-five patients were available for analyses. Median age was 60 [25th-75th percentile: 50-69] years, 27% were female, and median SOFA score was 12 [11-14] points. Serum suPAR levels were significantly associated with ICU mortality in univariable logistic regression analysis. There was no correlation between BALF and serum suPAR. Serum suPAR was higher in ARDS patients at 11.2 [8.0-17.2] ng/mL compared to those without ARDS at 7.1 [3.7-10.1] (p < 0.001). BALF-suPAR was significantly higher in patients with evidence of fungal lung infection compared to patients without fungal infection both in the general cohort (7.6 [3.2-9.4] vs 2.5 [1.1-5.3], p = 0.013) and in the subgroup of ARDS (7.2 [3.1-39.2] vs 2.5 [1.0-5.2], p = 0.022). All patients were classified as putative/probable invasive aspergillosis. CONCLUSION: We found significant higher levels of serum suPAR in ARDS patients compared to those not fulfilling ARDS criteria. Serum and BALF-suPAR were significantly higher in those patients with evidence for invasive pulmonary aspergillosis. These findings may suggest testing this biomarker for early diagnosis of fungal infection in a greater cohort.

Blood Biomarkers of Heart Failure and Hypercoagulation to Identify Atrial Fibrillation-Related Stroke.

Background and Purpose- Occult atrial fibrillation (AF) causes a relevant proportion of initially cryptogenic stroke (CS), but prolonged rhythm monitoring is difficult to apply to all such patients. We hypothesized that blood biomarkers indicating heart failure (NT-proBNP [N-terminal pro-brain natriuretic peptide]) and hypercoagulability (D-dimer, AT-III [antithrombin-III]) were associated with AF-related stroke and could serve to predict the likelihood of AF detection in CS patients early on. Methods- Over a 1-year period, we prospectively applied a defined etiologic work-up to all ischemic stroke patients admitted to our stroke unit. If no clear stroke cause was detected (CS), patients underwent extended in-hospital cardiac rhythm monitoring (≥72 hours). Blood to determine biomarker levels was drawn within 24 hours after admission. Results- Of 429 patients, 103 had AF-related stroke. Compared with noncardiac stroke patients (n=171), they had higher NT-proBNP (1867 versus 263 pg/ml) and D-dimer levels (1.1 versus 0.6 µg/ml), and lower AT-III concentration (89% versus 94%). NT-proBNP ≥505 pg/ml distinguished AF-related from noncardiac stroke with a sensitivity of 93% and a specificity of 72%. D-dimer and AT-III cutoffs had lower sensitivities (61% and 53%) and specificities (58% and 69%) for AF-related stroke. Of all initially 143 CS patients, 14 were diagnosed with AF during in-hospital monitoring. The preidentified NT-proBNP cutoff ≥505 pg/ml correctly predicted AF in 12 of them (86%, negative predictive value: 98%), while D-dimer and AT-III cutoffs were noncontributory. Conclusions- This study supports the association of NT-proBNP and to a lesser extent of hypercoagulation markers with AF-related stroke. NT-proBNP seems helpful in selecting CS patients for immediate extended cardiac rhythm monitoring to detect occult AF whereby levels <505 pg/ml seem to have a high-negative predictive value.

Calculation of HAS-BLED Score Is Useful for Early Identification of Venous Thromboembolism Patients at High Risk for Major Bleeding Events: A Prospective Outpatients Cohort Study.

The aim of this study was prospective evaluation of the performance of the HAS-BLED score in predicting major bleeding complications in a real-world outpatient cohort, during long-term anticoagulation for venous thromboembolism (VTE), treated with a broad spectrum of anticoagulants. We analyzed 111 outpatients objectively diagnosed with VTE and treated long-term with various anticoagulants. Patients were grouped in three cohorts based on the anticoagulant regimen. Calculation of the HAS-BLED score and documentation of bleeding events were performed every 6 months for 1 year. Patients with a HAS-BLED score ≥ 3 had an increased risk for major bleeding events (odds ratio [OR]: 13.05, 95% confidence interval [CI]: 0.96-692.58, p = 0.028) and a trend to higher risk for minor bleeding events as well (OR: 2.25, 95% CI: 0.87-5.85, p = 0.091) when compared with patients with a HAS-BLED score < 3.This indicates that a HAS-BLED score ≥ 3 allows for identification of patients with VTE on long-term anticoagulation at an increased risk for major bleeding events, irrespective of the anticoagulant agent used.

Activated protein C resistance assay and factor V Leiden.

The authors suggest that functional testing for activated protein C resistance is cheaper and more clinically relevant than genetic testing to detect a factor V Leiden mutation in identifying persons who are at risk for thromboembolism.

D-lactic acidosis - case report and review of the literature.

D-lactic acidosis is a rare complication that occurs mainly in patients with malabsorption due to a surgically altered gastrointestinal tract anatomy, namely in short bowel syndrome or after bariatric surgery. It is characterized by rapid development of neurological symptoms and severe metabolic acidosis, often with a high serum anion gap. Malabsorbed carbohydrates can be fermented by colonic microbiota capable of producing D-lactic acid. Routine clinical assessment of serum lactate covers only L-lactic acid; when clinical suspicion for D-lactic acidosis is high, special assays for D-lactic acid are called for. A serum level of more than 3 mmol/L of D-lactate confirms the diagnosis. Management includes correction of metabolic acidosis by intravenous bicarbonate, restriction of carbohydrates or fasting, and antibiotics to eliminate intestinal bacteria that produce D-lactic acid. We report a case of D-lactic acidosis in a patient with short bowel syndrome and review the pathophysiology of D-lactic acidosis with its biochemical and clinical features. D-lactic acidosis should be considered when patients with short bowel syndrome or other malabsorption syndromes due to an altered gastrointestinal tract anatomy present with metabolic acidosis and neurological symptoms that cannot be attributed to other causes. With the growing popularity of bariatric surgery, this metabolic derangement may be seen more frequently in the future.

Chemotherapy-Induced Intestinal Mucosal Barrier Damage: a Cause of Falsely Elevated Serum 1,3-Beta-d-Glucan Levels?

Blood citrulline and intestinal fatty acid binding protein were determined as biomarkers for intestinal mucositis. Biomarker levels were correlated with corresponding serum 1,3-beta-D-glucan levels in 56 samples obtained from 33 cases with underlying hematological malignancies receiving induction chemotherapy. No correlation between biomarkers of intestinal mucositis and BDG levels was observed. (This study has been registered at ClinicalTrials.gov under registration no. NCT01576653.).

Urine Galactomannan-to-Creatinine Ratio for Detection of Invasive Aspergillosis in Patients with Hematological Malignancies.

Galactomannan (GM) testing of urine specimens may provide important advantages, compared to serum testing, such as easy noninvasive sample collection. We evaluated a total of 632 serial urine samples from 71 patients with underlying hematological malignancies and found that the urine GM/creatinine ratio, i.e., (urine GM level × 100)/urine creatinine level, which takes urine dilution into account, reliably detected invasive aspergillosis and may be a promising diagnostic tool for patients with hematological malignancies. (This study has been registered at ClinicalTrials.gov under registration no. NCT01576653.).

Comparison of functional fibrinogen (FF/CFF) and FIBTEM in surgical patients - a retrospective study.

BACKGROUND: Fibrinogen-based clot firmness is reported as the maximum amplitude (MA) when using the citrated functional fibrinogen (CFF) assay in thrombelastography (TEG), and as the maximum clot firmness (MCF) together with several clot amplitude parameters when using the FIBTEM assay in thromboelastometry (ROTEM). Concern is currently being raised that these two tests have different platelet inhibiting performance and consequently provide different values. This is relevant for the clinical setting of fibrinogen replacement. We aim herein to compare the parameters of these two fibrinogen-based clot quality tests and their correlation with the plasma fibrinogen level as determined by the Clauss method. METHODS: In total 261 whole blood samples taken from 163 clinical routine surgical patients were analyzed with TEG 5000 and ROTEM tests, and correlation with Clauss fibrinogen level was assessed. RESULTS: Using TEG, the overall fibrin-based clot firmness measured in the CFF assay was significantly higher than the MCF measured by FIBTEM assay. Both assays showed significantly positive correlations with the fibrinogen levels measured using the Clauss method. However, individual values of Clauss fibrinogen concentration corresponded with different values for the two viscoelastometric tests; e.g. within the range of 1.9-2.1 g/L Clauss fibrinogen the median of CFF MA was 16.3 mm whereas FIBTEM MCF was 12.0 mm. CONCLUSIONS: We showed herein by measurements of citrated whole blood samples from surgical patients that CFF MA values were different from FIBTEM MCF values measured in the same sample. Awareness that these whole blood assays provide different clot amplitude results is mandatory, particularly if they are being considered as tools for guiding fibrinogen supplementation. Thromboembolic side effects caused by a potentially too high fibrinogen substitution must also kept in mind in this context.

Road and rail traffic noise induce comparable extra-aural effects as revealed during a short-term memory test.

To examine extraaural effects as induced by 20 min of road (ROAD) and 20 min of rail (RAIL) traffic noise with same loudness (75 dBA), a laboratory study was carried out. The study (N = 54) consisted of 28 high and 26 low-annoyed healthy individuals as determined by a traffic annoyance test. To control attention, all individuals performed a nonauditory short-term memory test during the noise exposures. A within-subject design, with phases of ROAD, RAIL, and CALM (memory test only), alternated by phases of rest, was defined. Heart rate (HR), systolic blood pressure (sBP), total peripheral resistance (TPR), as well as three autonomic variables, preejection period (PEP), 0.15-0.4 Hz high-frequency component of HR variability (HF), and salivary stress biomarker alpha amylase (sAA) were measured. In relation to CALM, HR increased (RAIL +2.1%, ROAD +2.5%), sBP tended to increase against the end of noise exposure, PEP decreased (RAIL -0.7%, ROAD -0.8%), HF decreased (RAIL -3.4%, ROAD -2.9%), and sAA increased (RAIL +78%, ROAD +69%). No differences were found between RAIL and ROAD, indicating that both noise stressors induced comparable extraaural effects. Factor annoyance showed significant during CALM. Here a reduced sympathetic drive (higher PEP values) combined with an increased vascular tone (higher TPR values) was found at the high-annoyed subgroup.

Elevated levels of interleukin 17A and kynurenine in candidemic patients, compared with levels in noncandidemic patients in the intensive care unit and those in healthy controls.

BACKGROUND: The interplay between Candida species and pattern recognition receptors, interleukins, kynurenine, and T cells has been studied in murine and ex vivo human studies, but data are lacking from patients with invasive fungal infections. Interleukin 17A (IL-17A) is considered an important component in host defense against Candida infections and is modulated by Candida-induced impairment of tryptophan-kynurenine metabolism. METHODS: Dectin-1, Toll-like receptor 2, and Toll-like receptor 4 expression; regulatory T cell (Treg) percentages; and interleukin 6, interleukin 10, IL-17A, interleukin 22, interleukin 23, interferon γ, kynurenine, and tryptophan levels were determined in candidemic patients and compared to levels in noncandidemic patients who are in the intensive care unit (ICU) and receiving antibiotic therapy and those in healthy controls, both with and without Candida colonization. RESULTS: Candidemic patients had significantly higher IL-17A and kynurenine levels, compared with noncandidemic patients, including Candida-colonized ICU patients and healthy controls. Within candidemic patients, time-dependent elevation of IL-17A and kynurenine levels was detected. IL-17A areas under the curve for differentiation between patients with early candidemia and those without candidemia (ICU patients, including Candida-colonized patients, and healthy controls) were between 0.94 (95% confidence interval [CI], .89-.99) and 0.99 (95% CI, .99-1). CONCLUSIONS: Candidemic patients had significantly higher IL-17A and kynurenine levels, compared with noncandidemic patients. The statistically significant association between IL-17A and kynurenine levels and candidemia suggests their potential as biomarkers for anticipation of invasive candidiasis. CLINICAL TRIALS REGISTRATION: NCT00786903.

Multicenter evaluation of a lateral-flow device test for diagnosing invasive pulmonary aspergillosis in ICU patients.

INTRODUCTION: The incidence of invasive pulmonary aspergillosis (IPA) in intensive care unit (ICU) patients is increasing, and early diagnosis of the disease and treatment with antifungal drugs is critical for patient survival. Serum biomarker tests for IPA typically give false-negative results in non-neutropenic patients, and galactomannan (GM) detection, the preferred diagnostic test for IPA using bronchoalveolar lavage (BAL), is often not readily available. Novel approaches to IPA detection in ICU patients are needed. In this multicenter study, we evaluated the performance of an Aspergillus lateral-flow device (LFD) test for BAL IPA detection in critically ill patients. METHODS: A total of 149 BAL samples from 133 ICU patients were included in this semiprospective study. Participating centers were the medical university hospitals of Graz, Vienna and Innsbruck in Austria and the University Hospital of Mannheim, Germany. Fungal infections were classified according to modified European Organization for Research and Treatment of Cancer/Mycoses Study Group criteria. RESULTS: Two patients (four BALs) had proven IPA, fourteen patients (sixteen BALs) had probable IPA, twenty patients (twenty-one BALs) had possible IPA and ninety-seven patients (one hundred eight BALs) did not fulfill IPA criteria. Sensitivity, specificity, negative predictive value, positive predictive value and diagnostic odds ratios for diagnosing proven and probable IPA using LFD tests of BAL were 80%, 81%, 96%, 44% and 17.6, respectively. Fungal BAL culture exhibited a sensitivity of 50% and a specificity of 85%. CONCLUSION: LFD tests of BAL showed promising results for IPA diagnosis in ICU patients. Furthermore, the LFD test can be performed easily and provides rapid results. Therefore, it may be a reliable alternative for IPA diagnosis in ICU patients if GM results are not rapidly available. TRIAL REGISTRATION: ClinicalTrials.gov NCT02058316. Registered 20 January 2014.

Novel tests for diagnosis of invasive aspergillosis in patients with underlying respiratory diseases.

RATIONALE: Invasive pulmonary aspergillosis has been increasingly reported in nonneutropenic patients, including those with underlying respiratory diseases. OBJECTIVES: We compared the diagnostic performances of galactomannan, 1,3-ß-D-glucan, and Aspergillus-specific lateral-flow device tests with that of conventional culture by using bronchoalveolar lavage fluid samples from patients with underlying respiratory diseases. METHODS: We analyzed 268 bronchoalveolar lavage samples from 221 patients with underlying respiratory diseases (and without hematologic malignancy or previous solid organ transplantation) that were collected for routine microbiological workup between February 2012 and May 2014 at the University Hospital of Graz, Austria. Invasive pulmonary aspergillosis was defined according to European Organization of Research and Treatment of Cancer/Mycoses Study Group criteria modified for patients with respiratory diseases. MEASUREMENTS AND MAIN RESULTS: Thirty-one patients (14%) had probable or proven, 25 possible, and the remaining 165 patients no invasive pulmonary aspergillosis. Probable/proven aspergillosis was associated with a significantly higher (P = 0.034) 30-day mortality rate of 32%. Sensitivities, specificities, and diagnostic odd ratios differed markedly between galactomannan (cut-off 0.5: optical density index, 0.97, 0.81, 124.4; cut-off 1.0: 0.97, 0.93, 422.1; cut-off 3.0: 0.61, 0.99, 109.8), ß-D-glucan (cut-off 80 pg/ml: 0.90, 0.42, 6.57; cut-off 200 pg/ml: 0.70, 0.61, 3.7), lateral-flow device tests (0.77, 0.92, 41.8), and mycological culture (0.29, 0.97, 14). CONCLUSIONS: Probable or proven invasive pulmonary aspergillosis was diagnosed in 14% of our study population and associated with significantly higher 30-day mortality rates. Although the performance of ß-D-glucan was limited by low specificity and that of mycological culture by low sensitivity, the Aspergillus lateral-flow device seems to be a promising alternative to galactomannan testing, which remains the diagnostic gold standard for aspergillosis. Clinical trial registered with www.clinicaltrials.gov (NCT 02058316).

Detection of (1→3)-ß-D-glucan in same-day urine and serum samples obtained from patients with haematological malignancies.

Serum 1,3-beta-d-glucan (BDG) testing is an established diagnostic marker for invasive fungal infections (IFI) among patients with haematological malignancies. In contrast limited data exist regarding the application of urine BDG testing. Same-day midstream urine and serum screening samples were collected in adult patients with underlying haematological malignancies. A total of 80 urine samples from 46 patients were investigated: Twenty-six had positive corresponding serum BDG >120 pg ml(-1), 27 intermediate (60-80 pg ml(-1)), and 27 negative serum BDG (<25 pg ml(-1)). A significant positive correlation between BDG in serum and urine samples was observed (P = 0.025; r = 0.252). Sensitivity, specificity, positive predictive value and negative predictive value (compared with same-day serum results) were: 42%, 76%, 46%, 73% when using an 80 pg ml(-1) urine cut-off, and 35%, 96%, 82%, 75% for a 250 pg ml(-1) cut-off. Urine BDG seemed to be higher in samples obtained from patients with probable IFI (n = 13, median 145, IQR 22-253) compared to those from patients without IFI (n = 56, median 24, IQR 15-88) but the difference was not significant (P = 0.069). Overall correlation of same-day urine BDG and serum BDG was moderate. However, urine BDG testing may warrant further investigation in larger studies, as high-positive urine results correlated with high-positive corresponding serum levels and clinical performance was comparable to serum BDG.

Diagnostic accuracy of the Aspergillus-specific bronchoalveolar lavage lateral-flow assay in haematological malignancy patients.

We evaluated the performance of the Aspergillus-specific lateral-flow device (LFD) test for diagnosing invasive pulmonary aspergillosis (IPA) in patients with underlying haematological malignancies. Participating centres were the two Austrian University Hospitals of Graz and Innsbruck. LFD performance was evaluated with 95 bronchoalveolar lavage fluid (BALF) samples from 72 patients collected prospectively in Graz, and with 24 BALF bio bank samples from 23 patients (21 samples with probable IPA) in Innsbruck. Invasive fungal infections were classified according to the revised European Organization of Research and Treatment of Cancer/Mycoses Study Group criteria. Overall, 27 patients (30 samples) had probable IPA, 32 (43 samples) possible and 36 (46 samples) did not fulfil IPA criteria. The vast majority of patients - in particular those with probable IPA - received mould-active treatment before bronchoscopy. Sensitivity, specificity, positive predictive value and negative-predictive-value for probable IPA diagnosis using the BALF-LFD test were 71%, 76%, 35% and 94% for the Graz cohort. Sensitivity of the BALF-LFD test for probable IPA was 57% in Innsbruck bio bank samples. Our results indicate that the BALF-LFD-test provides fast results with moderate sensitivities in patients with underlying haematological malignancies. Similar to other diagnostic tests and biomarkers sensitivity of the test may be influenced by ongoing systemic mould-active treatment.

Automation of serum (1→3)-beta-D-glucan testing allows reliable and rapid discrimination of patients with and without candidemia.

Testing for (1→3)-beta-D-glucan (BDG) is used for detection of invasive fungal infection. However, current assays lack automation and the ability to conduct rapid single-sample testing. The Fungitell assay was adopted for automation and evaluated using clinical samples from patients with culture-proven candidemia and from culture-negative controls in duplicate. A comparison with the standard assay protocol was made in order to establish analytical specifications. With the automated protocol, the analytical measuring range was 8-2500 pg/ml of BDG, and precision testing resulted in coefficients of variation that ranged from 3.0% to 5.5%. Samples from 15 patients with culture-proven candidemia and 94 culture-negative samples were evaluated. All culture-proven samples showed BDG values >80 pg/ml (mean 1247 pg/ml; range, 116-2990 pg/ml), which were considered positive. Of the 94 culture-negative samples, 92 had BDG values <60 pg/ml (mean, 28 pg/ml), which were considered to be negative, and 2 samples were false-positive (≥80 pg/ml; up to 124 pg/ml). Results could be obtained within 45 min and showed excellent agreement with results obtained with the standard assay protocol. The automated Fungitell assay proved to be reliable and rapid for diagnosis of candidemia. It was demonstrated to be feasible and cost efficient for both single-sample and large-scale testing of serum BDG. Its 1-h time-to-result will allow better support for clinicians in the management of antifungal therapy.