Search

Low attention has generally been dedicated to the influence of clinical presentation, extent of venous thrombosis and presence of residual vein obstruction (RVO) on the decision about the duration of secondary prophylaxis after a first venous thromboembolism (VTE).This study aimed at investigating the role of the mentioned VTE characteristics on the therapeutic decision using the information collected in the international, prospective, observational WHITE study.1240 patients were recruited by 79 clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia). 35 patients had as index event a pulmonary embolism (PE) without a deep vein thrombosis (DVT), and all continued anticoagulation. We focused on the 1205 subjects with DVT. The treatment decision differed among countries; altogether, more than 85% of patients with proximal (with or without distal) DVT continued a prophylactic treatment with anticoagulants, or antithrombotics; 34% of patients with isolated distal DVT stopped treatment, and more than 85% of patients with a PE associated to a DVT continued treatment. At multivariable analysis, the presence of proximal DVT, signs of post-thrombotic syndrome (PTS), residual vein obstruction (RVO), maintenance180 days and concomitant diseases was associated with increased probability to continue secondary prophylaxis.The presentation as proximal DVT (with or without PE) or isolated PE influenced the treating physicians' decision in favor of extension of secondary prophylaxis, together with the presence of concomitant diseases and local conditions which may increase the risk of post-thrombotic syndrome.

The decision on treatment after a first venous thromboembolism (VTE) to prevent recurrences may be influenced by many factors. The prospective, observational, WHITE study aimed to analyze how this issue was tackled in every-day clinical practice in various countries, which have sensibly different socio-economic conditions and healthcare systems. Doctors active in 79 Internal or Vascular clinical centers in 7 countries (China, Czechia, Poland, Portugal, Russia, Slovakia, and Tunisia) enrolled VTE patients after the maintenance treatment phase. The present report analyzed information, collected in the central database, regarding the baseline characteristics, index events, type and duration of anticoagulant therapy and decision on post-maintenance treatment. From April 2018 to December 2020, 1240 patients were enrolled, 58% with an unprovoked index event. Direct oral anticoagulants (DOACs) were used in > 85% of all cases in China, Poland, Portugal, Russia and Czechia, in 52% in Slovakia and in no patient in Tunisia. The maintenance anticoagulation lasted in average approximately 6 months. Altogether, anticoagulation was stopped in 20%, extended in about 50%, regardless of whether the event was unprovoked or provoked and shifted to antithrombotics (mainly sulodexide or aspirin) in the remaining patients. In conclusion, some differences in VTE patient management were found between countries. The provoked/unprovoked nature of the index event, instead, was not the prevalent criterion to drive the decision on extension of anticoagulation, without large variations between countries. DOACs were the most widely used anticoagulant drugs, whereas > 25% of patients received antithrombotic drugs instead of anticoagulants as extended treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s11739-021-02765-1.

Introduction: Co-administration of enoxaparin and a direct oral factor Xa inhibitor (xabans: apixaban, edoxaban, rivaroxaban) could give rise to the problem of overlapping the anti-Xa activity when measuring direct oral anticoagulant (DOAC) levels. We aimed to evaluate in vitro the degree of the interference of increasing enoxaparin concentrations on xaban plasma levels measured by different chromogenic anti-Xa assays with drug-specific calibrators and controls. Methods: Seven plasma samples were spiked with apixaban, edoxaban, or rivaroxaban at fixed concentration, and enoxaparin at increasing concentrations (0, 0.125, 0.250, 0.50, 1.0, 1.50, and 2.0IU/mL). The evaluated chromogenic assays were as follows: Biophen DiXaI and Biophen Heparin LRT (Hyphen BioMed), Berichrom Heparin and Innovance Heparin (Siemens), STA-Liquid Anti-Xa (Stago Diagnostics), Technochrom anti-Xa (Technoclone), and HemosIL Liquid Anti-Xa (Werfen). Results: The presence of enoxaparin caused increased DOAC levels, with over-estimation depending on the anti-Xa assay and on the heparin concentration in the sample. The smallest over-estimation was in the sample with enoxaparin 0.125IU/mL and the greatest in the sample with enoxaparin 2.0IU/mL (0%, 3.1%, and 7.4% vs 583.8%, 526.1%, and 415.2% for apixaban, edoxaban, and rivaroxaban, respectively). Biophen DiXaI showed lower interference compared to other methods (maximum over-estimation in the presence of enoxaparin 2.0IU/mL: 56.4% dosing rivaroxaban by Biophen DIXaI vs 583.8% dosing apixaban by Berichrom Heparin). Conclusion: The presence of enoxaparin interferes with xabans measurement by chromogenic anti-Xa assays causing falsely elevated DOAC levels, the over-estimation being dependent on the anti-Xa assay and on the heparin concentration in the sample.

Essentials Between-lab variations of cut-off values in lupus anticoagulant detection are unknown. Cut-off values were calculated in 11 labs each testing plasma from 120 donors with 3 platforms. Major variation was observed even within the same platform. Cut-off values determined in different labs are not interchangeable. SummaryBackground Cut-off values for interpretation of lupus anticoagulant (LA) detection are poorly investigated. Aims (i) To assess whether results from healthy donors were normally distributed and (ii) the between-laboratories differences in cut-off values for screening, mixing and LA confirmation when calculated as 99th or 95th centiles, and (iii) to assess their impact on the detection rate for LA. Methods Each of 11 laboratories using one of the three widely used commercial platforms for LA detection was asked to collect plasmas from 120 healthy donors and to perform screening, mixing and LA confirmation with two methods (activated partial thromboplastin time [APTT] and dilute Russell viper venom [dRVV]). A common set of LA-positive or LA-negative freeze-dried plasmas was used to assess the LA detection rate. Results were centralized (Milano) for statistical analysis. Results and conclusions (i) Clotting times or ratios for healthy subjects were not normally distributed in the majority of cases. The take-home message is that cut-off values should be determined preferably by the non-parametric method based on centiles. (ii) There were relatively large inter-laboratory cut-off variations even within the same platform and the variability was marginally attenuated when results were expressed as ratios (test-to-normal pooled plasma). The take-home message is that cut-off values should be determined locally. (iii) There were differences between cut-off values calculated as 99th or 95th centiles that translate into a different LA detection rate (the lower the centile the greater the detection rate). The take-home message is that cut-off values determined as the 95th centile allow a better LA detection rate.

Introduction: Several specific assays are commercially available to determine dabigatran anticoagulant activity. Aims of this multicenter and multiplatform study were to compare five methods for dabigatran measurement and investigate their performances in the low concentration range. Methods: Dabigatran levels were analyzed in 295 plasma samples from patients enrolled in the START-Laboratory Register by the following methods using dedicated calibrators and controls: STA-ECA II (Diagnostica Stago), standard and low range Hemoclot Thrombin Inhibitors (Hyphen BioMed), Direct Thrombin Inhibitor Assay (Instrumentation Laboratory), Direct Thrombin Inhibitor Assay (Siemens), Technoclot DTI (Technoclone). Results: Methods showed variable agreement with the Hemoclot Thrombin Inhibitors assay used as reference test, with modest under- or overestimations (Bland-Altman bias from −17.3 to 4.0 ng/mL). Limits of detection and quantification varied depending on the assay (4-52 and 7-82 ng/mL, respectively). Between-run precision and accuracy were good for all methods for both quality control levels. Assay's repeatability assessed at very low dabigatran concentrations (from 10 to 60 ng/mL) was also acceptable, variability generally increased at lower drug levels. Conclusion: The five dabigatran-specific assays evaluated in this study provided reliable assessment of dabigatran plasma levels, although showing different performances. © 2018 The Authors. International Journal of Laboratory Hematology Published by John Wiley & Sons Ltd

Essentials Prothrombin and partial thromboplastin time (PT/PTT) measure direct oral anticoagulants (DOACs). PT, PTT and specific tests for DOACs were performed on patients treated for atrial fibrillation. Normal PT/PTT don't exclude DOAC activity and their prolongation doesn't confirm DOAC action. The use of PT or PTT to evaluate DOAC activity could cause dangerous misinterpretations. Summary: Background Prothrombin time (PT) and activated partial thromboplastin time (APTT) have been proposed to measure the effect of oral anti-activated factor X (FXa) or anti-activated FII drugs, respectively. Aims To evaluate the relationships and responsiveness of PT and APTT versus direct oral anticoagulant (DOAC) concentrations measured with specific coagulation tests performed with different platforms in four Italian anticoagulation clinics. Methods Six hundred and thirty-five patients with atrial fibrillation participated in the study: 240 were receiving dabigatran, 264 were receiving rivaroxaban, and 131 were receiving apixaban. Blood was taken at trough and peak within the first month (15–25 days) of treatment. PT, APTT, diluted thrombin time (dTT) calibrated for dabigatran and anti-FXa calibrated for rivaroxaban or apixaban were determined. Results For dabigatran, the correlation between APTT and dTT ranged from r = 0.80 to r = 0.62. For rivaroxaban, the correlation between the anti-FXa assay and PT ranged from r = 0.91 to r = 0.73. For apixaban, the correlation between the anti-FXa assay and PT was lower than for the two other drugs (r = 0.81 to r = 0.54). Despite the above significant correlations, the responsiveness of PT or APTT was relatively poor. A discrepancy between global testing and DOAC plasma concentrations was shown in a considerable proportion of patients, depending on the platform and drug, with values ranging from 6% to 62%. Conclusions Overall, poor responsiveness of the screening tests to DOAC concentrations was observed. PT and APTT normal values cannot exclude DOAC anticoagulant activity, and PT or APTT prolongation is not always associated with DOAC anticoagulant effect as determined with specific tests.

Dear Sirs, Skov et al. object that the effect of the variant allele rs7294 which is associated with higher warfarin requirements is not relevant in our dosing algorithm, its effect being significant at the univariate but not at the multivariate analysis. Skov et al. also show that there is not a complete linkage disequilibrium but a significant correlation between rs 7294 and the variant allele rs 9934438 which is associated with warfarin sensitivity, based on the data of their study [1]. The frequency of the variant allele rs 7294 was 9.6% in their study vs 7.3% in our derivation group and 10% in the validation group. The partial linkage disequilibrium between the rs 7294 and the rs 9934438 is also consistent with data previously published by Wadelius et al [2]. In the algorithm recently elaborated by Pavani et al. [3], various parameters were included in the multiple linear regression model, and they concluded that the incorporation of VKORC1*3 (rs 7294) and VKORC1*4 (6009 C/T) could help in a precise prediction of therapeutic warfarin dose. Moreover, in a recent meta-analysis [4], Jorgensen et al. showed that for the Caucasian ethnic group, the pooled effect estimate of the VKORC SNP rs 7294 on warfarin dosing was nonsignificant for heterozygotes versus wild-types, but was statistically significant for mutant-types versus wild-types. In our study [5], we chose to employ a simultaneous multivariate regression as our analysis was exploratory and hypothesis generating. The loss of significance of the effect of rs 7294 at the multivariate analysis could be due to our limited sample size, as acknowledged in our discussion, and larger studies are required to confirm our algorithm.

Background: Pretest clinical probability with the Wells rule and D-dimer have been widely investigated for the diagnosis of symptomatic proximal deep vein thrombosis (DVT) of the lower limbs, but they have not been formally tested for symptomatic isolated distal DVT diagnosis. Objective: To evaluate the diagnostic accuracy of the Wells rule and D-dimer for isolated distal DVT. Design, Setting, and Patients: This was a single-center, cross-sectional study including 873 consecutive outpatients with suspected DVT, in whom pretest clinical probability determination, D-dimer determination (STA Liatest; cut-off of 95% for isolated distal DVT. not available

Summary. Background and Aim: Several factors are associated with an increased risk of recurrent venous thromboembolism (VTE). The aim of the study was to investigate whether the quality of oral anticoagulation therapy (OAT) is a long-term risk factor for recurrence of VTE after OAT interruption. Methods and results: A total of 297 patients (170 males) with a recent acute unprovoked VTE episode were prospectively monitored during OAT in our anticoagulation clinic and followed up for 21 months after OAT interruption. Recurrent events were recorded in 42 subjects for 493 years of follow-up [14.1% of patients; 8.5% patient-years (pt-y)] after OAT withdrawal. The rate of recurrence was not correlated to OAT duration. Subjects experiencing recurrence after OAT interruption had spent significantly more time at markedly subtherapeutic international normalized ratio (INR) levels (

High levels of factor VIII are a common risk factor for venous thromboembolism (VTE). The aim of this study was to evaluate the possible interaction between the presence of high factor VIII levels and oral contraceptive (OC) use.Factor VIII levels were measured by a chromogenic assay in 174 women who suffered from VTE in reproductive age and in 484 healthy women. Subjects carrying thrombophilic alterations were excluded.Factor VIII levels were stratified into quartiles. The adjusted odds ratio (OR) of VTE in subjects with factor VIII levels in the upper quartile (1.95 IU/mL) was 7.45 (95%CI: 3.80-14.6). Among the 174 patients, 85 had experienced VTE during OC use. The 179 healthy women who had used OC for at least 6 months in the two years before presentation but had stopped OC at least 3 months before the blood sampling were considered as OC users. The risk of VTE among OC users with factor VIII levels in the upper quartile was increased about 13-fold (OR: 13.0, 95% CI: 4.92-34.3).Our results showed that there is an increased risk of VTE due to oral contraceptive use in women with elevated factor VIII and, as has been previously described for factor V Leiden and G20210A prothrombin mutations, the raised level of the coagulation factor and oral contraceptive use seem to have a synergistic effect.

Thalidomide has emerged as an active agent for the management of advanced multiple myeloma (MM) and is currently under investigation also in patients with newly diagnosed disease.[1][1] It is relatively well tolerated; more common side effects include constipation, sedation, skin rash, fatigue, and

Objectives To assess the possible association between inherited thrombophilic alterations and the severity of peripheral arterial disease (PAD). Design A case-control study. Methods We evaluated the presence of G20210A prothrombin (FII) and R506Q FV Leiden mutations, antithrombin, protein C and S deficiencies in 176 patients with PAD at Fontaine's stage II and in 106 patients with critical limb ischaemia (Fontaine's stage III/IV) consecutively referred to our unit. As control group, we studied 209 apparently healthy subjects. Results The prevalence of G20210A prothrombin mutation was similar in PAD patients and controls (odds ratio (OR): 1.361; 95% confidence interval (CI): 0.552–3.355; p = 0.503 after adjustment for age, sex, smoking and presence of diabetes), but was significantly higher in patients with Fontaine's stage III/IV vs. those with stage II and controls (10.4% vs. 3.4% vs. 4.3%; p = 0.02, respectively). According to a logistic multivariate model that included all patients with PAD, the presence of the FII G20210A mutation (OR: 4.621; 95% CI: 1.548–13.789; p = 0.006) was associated with critical limb ischaemia after adjustment for age, sex, smoking, presence of diabetes and the use of platelet aggregation inhibitors. The prevalence of the other thrombophilic alterations was not different in patients with Fontaine's stage III/IV, in patients with stage II and in controls. Conclusion These hypothesis-generating data suggest that the FII 20210A allele may be considered as a genetic marker predisposing critical ischaemia in patients with PAD, justifying larger longitudinal studies.