Essentials
Direct oral anticoagulants (DOACs) do not require laboratory monitoring currently.
DOAC specific measurements were performed at trough in patients with atrial fibrillation.
Patients who ...developed thromboembolic events showed lower DOAC plasma levels.
This study supports the concept of measuring DOAC levels at steady state.
Summary
Background
Direct oral anticoagulants (DOACs) are administered at fixed doses without the need for dose adjustment according to laboratory testing. High interindividual variability in drug blood levels has been shown with all DOACs. To evaluate a possible relationship between DOAC C‐trough anticoagulant levels and thromboembolic events, 565 consecutive naive patients with atrial fibrillation (AF) were enrolled in this study performed within the START Laboratory Registry.
Methods
DOAC‐specific measurements (diluted thrombin time or anti‐activated factor II calibrated for dabigatran; anti‐activated FX calibrated for rivaroxaban or apixaban) at C‐trough were performed locally at steady state within 15–25 days after the start of treatment. For each DOAC, the interval of C‐trough levels, from the limit of quantification to the highest value, was subdivided into four equal classes, and results were attributed to these classes; the median values of results were also calculated. Thromboembolic complications occurring during 1 year of follow‐up were recorded.
Results
Thromboembolic events (1.8%) occurred in 10 patients who had baseline C‐trough levels in the lowest class of drug levels. The incidence of thromboembolic events among patients with DOAC C‐trough levels in the lowest level class was 2.4%, and that in the remaining groups was 0%. The patients with thrombotic complications also had a higher mean CHA2DS2‐VASc score than that of the total patient population: 5.3 (95% confidence interval CI 4.3–6.3 versus 3.0 (95% CI 2.9–3.1).
Conclusion
In this study cohort, thrombotic complications occurred only in DOAC‐treated AF patients who had very low C‐trough levels, with a relatively high CHA2DS2‐VASc score. Larger studies are warranted to confirm these preliminary observations.
Essentials
Tests for direct oral anticoagulants (DOACs) are not widely applied.
These tests are perceived to be difficult to run and subjected to large between‐lab variation.
We carried out ...proficiency testing surveys for DOAC testing in Italy.
Interlab variability was small and similar to that of the international normalised ratio.
Summary
Background
Tests for direct oral anticoagulants (DOACs) are not widely available. The perception that they are difficult to perform and are subject to large between‐laboratory variation makes their implementation difficult.
Aims
We carried out proficiency‐testing surveys for DOACs within the activity of the external quality‐assessment scheme of the Italian Federation of Thrombosis Centers.
Design
Participants were provided with coded freeze‐dried plasmas without or with graded concentrations of the three main DOACs, and asked to measure prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time and DOAC concentrations with dedicated tests. The results were centralized for statistical analysis.
Results and conclusions
All participants (n = 235) reported results for PT and APTT, and approximately one‐third reported results for DOAC concentration. PT and APTT showed variable responsiveness to DOACs: PT was more responsive to rivaroxaban than to dabigatran or apixaban. APTT was more responsive to dabigatran than to rivaroxaban or apixaban. The thrombin time ratio (test/normal) was close to unity for plasmas without dabigatran, and was high (i.e. 7.6‐fold or 15.4‐fold longer than the plasma free from the drug) for plasmas containing dabigatran at low (i.e. 42 ng mL−1) or high (i.e. 182 ng mL−1) concentration. Dedicated tests were responsive to the respective drugs, and their interlaboratory variability was relatively small (overall coefficients of variation of 8.7%, 8.4% or 10.3% for dabigatran, rivaroxaban and apixaban, respectively) and was comparable to that observed within the same survey for the International Normalized Ratio (i.e. 11.4%). In conclusion, tests for DOAC measurement performed reasonably well in a national quality‐control scheme. Regulatory authorities should urgently issue recommendations on their use, and clinical laboratories should make them available.
See also Galli M. The antiphospholipid triangle. This issue, pp 234–6.
Summary. Background: The characteristics and the clinical course of antiphospholipid syndrome (APS) in high‐risk patients that ...are positive for all three recommended tests that detect the presence of antiphospholipid (aPL) antibodies have not been described. Methods: This retrospective analysis of prospectively collected data examined patients referred to Italian Thrombosis Centers that were diagnosed with definite APS and tested positive for aPL lupus anticoagulant (LA), anti‐cardiolipin (aCL), and anti‐β2‐glycoprotein I (β2GPI) antibodies. Laboratory data were confirmed in a central reference laboratory. Results: One hundred and sixty patients were enrolled in this cohort study. The qualifying events at diagnosis were venous thromboembolism (76 cases; 47.5%), arterial thromboembolism (69 cases; 43.1%) and pregnancy morbidity (11 cases; 9.7%). The remaining four patients (2.5%) suffered from catastrophic APS. The cumulative incidence of thromboembolic events in the follow‐up period was 12.2% (95%CI, 9.6–14.8) after 1 year, 26.1% (95%CI, 22.3–29.9) after 5 years and 44.2% (95%CI, 38.6–49.8) after 10 years. This was significantly higher in those patients not taking oral anticoagulants as compared with those on treatment (HR=2.4 95%CI 1.3–4.1; P < 0.003). Major bleeding associated with oral anticoagulant therapy was low (0.8% patient/years). Ten patients died (seven were cardiovascular deaths). Conclusions: Patients with APS and triple positivity for aPL are at high risk of developing future thromboembolic events. Recurrence remains frequent despite the use of oral anticoagulants, which significantly reduces the risk of thromboembolism.
Summary
Introduction
D‐dimer assay, generally evaluated according to cutoff points calibrated for VTE exclusion, is used to estimate the individual risk of recurrence after a first idiopathic event ...of venous thromboembolism (VTE).
Methods
Commercial D‐dimer assays, evaluated according to predetermined cutoff levels for each assay, specific for age (lower in subjects <70 years) and gender (lower in males), were used in the recent DULCIS study. The present analysis compared the results obtained in the DULCIS with those that might have been had using the following different cutoff criteria: traditional cutoff for VTE exclusion, higher levels in subjects aged ≥60 years, or age multiplied by 10.
Results
In young subjects, the DULCIS low cutoff levels resulted in half the recurrent events that would have occurred using the other criteria. In elderly patients, the DULCIS results were similar to those calculated for the two age‐adjusted criteria. The adoption of traditional VTE exclusion criteria would have led to positive results in the large majority of elderly subjects, without a significant reduction in the rate of recurrent event.
Conclusion
The results confirm the usefulness of the cutoff levels used in DULCIS.
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.
Essentials
Predicting recurrences may guide therapy after unprovoked venous thromboembolism (VTE).
We evaluated the DASH score in 827 patients with unprovoked VTE to verify prediction accuracy.
A ...DASH score ≤ 1 had a cumulative recurrence risk at 1 year of 3.6%, as predicted by the model.
The DASH score performed better in younger (< 65 years old) subjects.
Summary
Background
The DASH prediction model has been proposed as a guide to identify patients at low risk of recurrence of venous thromboembolism (VTE), but has never been validated in an independent cohort.
Aims
To validate the calibration and discrimination of the DASH prediction model, and to evaluate the DASH score in a predefined patient subgroup aged > 65 years.
Methods
Patients with a proximal unprovoked deep vein thrombosis (DVT) or pulmonary embolism (PE) who received a full course of vitamin K antagonist or direct oral anticoagulant (> 3 months) and had D‐dimer measured after treatment withdrawal were eligible. The DASH score was computed on the basis of the D‐dimer level after therapy withdrawal and personal characteristics at the time of the event. Recurrent VTE events were symptomatic proximal or distal DVT/PE, and were analyzed with a time‐dependent analysis. Observed 12‐month and 24‐month recurrence rates were compared with recurrence rates predicted by the DASH model.
Results
We analyzed a total of 827 patients, of whom 100 (12.1%) had an objectively documented recurrence. As compared with the original DASH cohort, there was a greater proportion of subjects with a ‘low‐risk’ (≤ 1) DASH score (66.3% versus 51.6%, P < 0.001). The slope of the observed versus expected cumulative incidence at 2 years was 0.71 (95% confidence interval 0.51–1.45). The c‐statistic was lower for subjects aged > 65 years (0.54) than for younger subjects (0.72).
Conclusions
These results confirm the validity of DASH prediction model, particularly in young subjects. The recurrence risk in elderly patients (> 65 years) was, however, > 5% even in those with the lowest DASH scores.
Whether antibodies directed to β2-Glycoprotein I (aβ2GPI) are responsible for LA activity is not well defined. However, in the absence of such antibodies the molecule responsible for LA phenomenon is ...unknown.
The aim of this study was the biochemical identification of the target antigen epitope of aPL responsible of LA activity in the absence of aβ2GPI antibodies together with the biological and clinical characteristics of these patients in comparison with classical triple positive patients.
A comparison of patients with LA without (LA+/aβ2GPI−) and those with (LA+/aβ2GPI+) associated aβ2GPI antibodies was performed. Size exclusion chromatography and analytical chromatography were used to identify the molecule with LA activity in patients LA+/aβ2GPI-.
Analytical size-exclusion chromatography revealed a peak of 996Kd with LA activity perfectly overlapping that of IgM anti phosphatidylserine/prothrombin (aPS/PT) antibodies. Similarly, all the 25 LA+/aβ2GPI− patients were positive for aPS/PT antibodies. LA+/aβ2GPI− compared to 33 LA+/aβ2GPI+ patients turned out to be significantly older, with a lower rate of previous thromboembolic events and a weaker LA activity. Search for aPS/PT and aβ2GPI antibodies in patients with LA is useful to identify two subgroups of LA at different risk of thromboembolic events.
•Isolated LA (LA+,aβ2GPI-) shows a peculiar pattern of antiphospholipid antibodies (aPS/PT usually of IgM isotype).•Isolated LA are older, at lower thrombotic risk, and have a weaker LA potency with respect to LA+/aβ2GPI+.•The distinction is useful in clinical practice when deciding the appropriate treatment.
The aim of the present study was to retrospectively compare the outcomes of two minimally invasive surgical techniques in patients with isolated anterior talofibular ligament (ATFL) lesion suffering ...from chronic ankle instability (CAI).
Thirty-six patients with ATFL lesion suffering from CAI were treated at our department from 2010 to 2017 and retrospectively reviewed after an average time of 4 years (2 to 9 years). Eighteen patients underwent a four-step operative protocol, including: synovectomy, debridement of ATFL lesion borders, capsular shrinkage, and 21-day immobilization and non-weightbearing. Eighteen patients underwent arthroscopic Broström procedure. Patients were assessed pre-operatively and at follow-up with American Orthopedic Foot & Ankle Society Score (AOFAS) scale, Karlsson-Peterson score, Tegner activity level, and objective examination comprehending range of motion, anterior drawer test, and talar tilt test. Wilcoxon test was utilized to compare the pre-operative and follow-up status. The Mann-Whitney U test was used to make comparisons between the two surgical techniques. Statistical significance was established at p < 0.05.
Mean overall AOFAS, Karlsson-Peterson and Tegner scores significantly increased at follow-up compared to pre-operatory status (p < 0.05). However, no statistically significant differences concerning mean AOFAS score (90.2 in the four-step group vs. 89.2 in the Broström arthroscopic group), mean Karlsson-Peterson score (88.1 and 85.9 respectively), and median Tegner activity level (6.0 vs. 5.5) were reported between the two groups (p = n.s.). The complications in the arthroscopic four-step treatment group included damage to the superficial branch of the peroneal nerve in one case. The complications in the arthroscopic Broström included nerve injury in one case and persistent local pain nearby suture knot in one case.
Both arthroscopic Broström and a four-step operative procedure including synovectomy, debridement of ATFL lesion borders, capsular shrinkage and immobilization, improved functional outcomes in patients with ATFL lesion suffering from CAI.
Background: The assessment of the risk of recurrent venous thromboembolism (VTE) is important to determine the optimal duration of secondary prophylaxis. The risk can be estimated by measuring ...individual parameters reflecting hypercoagulability. Because of the large numbers of such putative parameters, the assessment in individual patients is complex. Application of global assays reflecting the pro‐/anti‐coagulant balance in vivo would be desirable. Objectives: To investigate the relationship between recurrent VTE and thrombin generation (TG). Patients‐methods: Two hundred and fifty‐four patients were followed‐up after a first episode of unprovoked, objectively documented VTE for a period of 2.7 years after discontinuation of treatment with vitamin K antagonists. TG was measured 1 month after discontinuation of treatment as endogenous thrombin potential (ETP), peak thrombin and lag‐time in the presence or absence of thrombomodulin. The study outcome was objectively documented symptomatic recurrent VTE. Results: Patients with ETP or peak (measured in the presence of thrombomodulin) of >960 nm*min or >193 nm had hazard ratios (HR) (95% CI) for recurrent VTE of 3.41 (1.34–8.68) or 4.57 (1.70–12.2) as compared with those with an ETP <563 nm*min or peak <115 nm. Patients with lag‐time <14.5 min had HR of 3.19 (1.29–7.89) as compared with those with lag‐time >20.8 min. HR for ETP, peak or lag‐time measured in the absence of thrombomodulin were smaller than those measured in the presence of thrombomodulin. Conclusions: The measurement of TG helps to identify patients at higher risk of VTE recurrence. The increased risk may be better appreciated if the test is performed in the presence of thrombomodulin.
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