Diagnostic accuracy of four different D-dimer assays: a post-hoc analysis of the YEARS study

Introduction: For exclusion of pulmonary embolism (PE) clinical decision rules in combination with a D-dimer assay are applied. Currently available D-dimer assays are not standardized and it is unknown whether these differences have an impact on diagnostic management of suspected PE. Therefore, the aim is to explore differences between D-dimer assays and their impact on diagnostic outcome. Methods: Data from all patients included in the YEARS study were collected. The YEARS study is a prospective, multicentre, cohort outcome study evaluating 3462 patients with suspected PE in which four different D-dimer assays were applied (Liatest, Innovance, Tinaquant, Vidas). Median D-dimer concentrations were calculated for each D-dimer assay. Sensitivity, specificity, PPV and NPV for detection of PE of all four assays were determined in patients without YEARS items and in those with >1 YEARS items (i.e. symptomatic deep vein thrombosis, haemoptysis, and whether PE is the most likely diagnosis). Results: A total of 1323, 1100, 768 and 271 D-dimer concentrations were collected using the Liatest Innovance, Tinaquant and Vidas assay, respectively. Median D-dimer concentrations differed significantly between assays, with lowest values in the Tinaquant assay. In patients without YEARS items using a cutoff level of 1000 ng/mL, the NPV varied from 99,5 to 100%. In patients with >1 YEARS items using a 500 ng/mL cutoff, the NPV varied from 97,0 to 100% depending on the assay. Conclusions: The overall high NPV for all assays demonstrates the clinical value of the D-dimer assay. However, these results confirm differences between D-dimer assays, which have an impact on follow-up imaging. This emphasizes the need for standardization of D-dimer assays.Experimentele farmacotherapi

Veneuze trombo-embolie : wanneer zijn laboratoriumtesten voor trombofilie zinvol?

Laboratoriumtesten voor trombofilieonderzoek worden vaak door de kliniek aangevraagd na het optreden van veneuze trombo-embolie. Indien afwijkingen worden gevonden leidt dit niet altijd tot klinische consequenties, zoals verlenging van antistollingstherapie. In de eind 2007 vastgestelde CBO-richtlijn ‘diagnostiek, preventie en behandeling van veneuze trombo-embolie en secundaire preventie arteriële trombose’ staan wetenschappelijk onderbouwde richtlijnen beschreven voor situaties waarbij het bepalen van trombofiliefactoren zinvol is en invloed heeft op het klinisch handelen. In dit artikel wordt de consequentie van deze richtlijn voor de laboratoria beschreven. Grofweg komt het erop neer dat voor de meeste patiënten met een eerste of recidief veneuze trombo-embolie het bepalen van trombofiliefactoren anders dan antifosfolipide-antistoffen geen therapeutische consequenties heeft en daarom wordt afgeraden. Slechts in uitzonderlijke gevallen wordt het bepalen van trombofiliefactoren wel overwogen. Daarbij is het van belang dat rekening gehouden wordt met preanalytische factoren die de uitslag van trombofilietesten kunnen beïnvloeden

Hb Nouakchott [114(GH2)ProLeu; HBA1: c.344C > T], A Second and Third Case Described in Two Unrelated Dutch Families

Genetics of disease, diagnosis and treatmen

The performance of the platelet function analyzer is insufficient to reliably diagnose an increased bleeding tendency in children and adult patients

Despite widespread use of the Platelet Function Analyzer-100 closure time (PFA) as alternative to the bleeding time (BT) for the analysis of primary hemostasis defects, the predictive value is highly variable. This may partly be due to the lack of larger studies, especially in children. We assessed the sensitivity and specificity of the PFA and BT in a large number of patients with increased bleeding tendency due to von Willebrand disease (vWD) and other platelet function disorders (PFD). In addition, we analysed the effect of desmopressin on the PFA in these patients. Methods: PFA and/or BT were measured in a total of 1027 patients (484 children) with increased bleeding tendency. The final diagnosis was ascertained by measurement of specific platelet function tests or clotting factor levels. We also analysed the effect of treatment with 0.3 ig/kg desmopressin on the PFA. Results: Sensitivity and specificity of the PFA were moderate, with no clear differences between children and adults with vWD (Table). The detection of PFD with the PFA was better in children than in adults. The sensitivity of the BT was comparable to the PFA, but the specificity in children was very low. In 54 patients, desmopressin treatment significantly shortened PFA except for one patient with M. Glanzmann and one with vWD. Table represented. Conclusion: Based on this large cohort, the predictive value of the PFA and BT for PFD and vWD in children and adults with increased bleeding tendency is insufficient. The BT had a comparable sensitivity, whereas its specificity was lower than that for PFA, especially in children. PFA seems suitable for measuring the effect of desmopressin

Direct oral anticoagulant blood level monitoring in daily practice

Introduction: Routine monitoring is not required in direct oral anticoagulant (DOAC) treatment, yet it is frequently performed. Guidance on the interpretation and management of DOAC level measurements is lacking and it is key to investigate which patients would benefit from monitoring. Our aims were to investigate why DOAC levels are requested and if they lead to changes in anticoagulant management. Methods: We retrospectively collected all clinically requested DOAC levels from 2012 until 2019 in two Dutch academic hospitals. Clinical data with regard to the first DOAC level of every patient was collected by chart review. Primary outcomes were settings, indications and changes in anticoagulant management of DOAC level measurement. In addition, we compared demographic and clinical characteristics in patients with and without changes in anticoagulant management. Results: In total, we included 604 DOAC levels. The majority was requested in an outpatient setting by the department of internal medicine. In 270 (45%) cases we identified a patient specific indication, with evaluation of DOAC accumulation being the most frequently requested. Of all 604 DOAC levels, 159 (26%) were followed by changes in anticoagulation management. The large majority of changes occurred in patients that had a patient specific indication. Patients who underwent changes were older and had more comorbidity than patients who did not (n ​= ​445). Conclusion: Almost half of the DOAC levels with a specific indication for monitoring were followed by a change in anticoagulant management. Future studies should investigate the relation between DOAC levels, the changes in anticoagulant management and clinical outcomes

Harmonizing light transmission aggregometry in the Netherlands by implementation of the SSC-ISTH guideline

Light transmission aggregometry (LTA) is considered the gold standard method for evaluation of platelet function. However, there are a lot of variation in protocols (pre-analytical procedures and agonist concentrations) and results. The aim of our study was to establish a national LTA protocol, to investigate the effect of standardization and to define national reference values for LTA. The SSC guideline was used as base for a national procedure. Almost all recommendations of the SSC were followed e.g. no adjustment of PRP, citrate concentration of 109 mM, 21 needle gauge, fasting, resting time for whole blood and PRP, centrifugation time, speed and agonists concentrations. LTA of healthy volunteers was measured in a total of 16 hospitals with 5 hospitals before and after standardization. Results of more than 120 healthy volunteers (maximum aggregation %) were collected, with participating laboratories using 4 different analyzers with different reagents. Use of low agonist concentrations showed high variation before and after standardization, with the exception of collagen. For most high agonist concentrations (ADP, collagen, ristocetin, epinephrine and arachidonic acid) variability in healthy subjects decreased after standardization. We can conclude that a standardized Dutch protocol for LTA, based on the SSC guideline, does not result in smaller variability in healthy volunteers for all agonist concentrations

IN02, A Positive Regulator of Lipid Biosynthesis, Is Essential for the Formation of Inducible Membranes in Yeast

Expression of the 180-kDa canine ribosome receptor in Saccharomyces cerevisiae leads to the accumulation of ER-like membranes. Gene expression patterns in strains expressing various forms of p180, each of which gives rise to unique membrane morphologies, were surveyed by microarray analysis. Several genes whose products regulate phospholipid biosynthesis were determined by Northern blotting to be differentially expressed in all strains that undergo membrane proliferation. Of these, the INO2 gene product was found to be essential for formation of p180-inducible membranes. Expression of p180 in ino2Δ cells failed to give rise to the p180-induced membrane proliferation seen in wild-type cells, whereas p180 expression in ino4Δ cells gave rise to membranes indistinguishable from wild type. Thus, Ino2p is required for the formation of p180-induced membranes and, in this case, appears to be functional in the absence of its putative binding partner, Ino4p