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.

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.

The optimal duration of oral anticoagulation in patients with idiopathic venous thromboembolism is uncertain. Testing of d-dimer levels may play a role in the assessment of the need for prolonged anticoagulation. We performed d-dimer testing 1 month after the discontinuation of anticoagulation in patients with a first unprovoked proximal deep-vein thrombosis or pulmonary embolism who had received a vitamin K antagonist for at least 3 months. Patients with a normal d-dimer level did not resume anticoagulation, whereas those with an abnormal d-dimer level were randomly assigned either to resume or to discontinue treatment. The study outcome was the composite of recurrent venous thromboembolism and major bleeding during an average follow-up of 1.4 years. The d-dimer assay was abnormal in 223 of 608 patients (36.7%). A total of 18 events occurred among the 120 patients who stopped anticoagulation (15.0%), as compared with 3 events among the 103 patients who resumed anticoagulation (2.9%), for an adjusted hazard ratio of 4.26 (95% confidence interval [CI], 1.23 to 14.6; P=0.02). Thromboembolism recurred in 24 of 385 patients with a normal d-dimer level (6.2%). Among patients who stopped anticoagulation, the adjusted hazard ratio for recurrent thromboembolism among those with an abnormal d-dimer level, as compared with those with a normal d-dimer level, was 2.27 (95% CI, 1.15 to 4.46; P=0.02). Patients with an abnormal d-dimer level 1 month after the discontinuation of anticoagulation have a significant incidence of recurrent venous thromboembolism, which is reduced by the resumption of anticoagulation. The optimal course of anticoagulation in patients with a normal d-dimer level has not been clearly established. (ClinicalTrials.gov number, NCT00264277.)

Persistent antiphospholipid (aPL) antibodies are occasionally found in subjects without prior history of thromboembolic events (TEs), raising the dilemma of whether to initiate or not a primary thromboprophylaxis. A first TE is considered rare in aPL carriers, but previous studies did not consider the aPL profile nor was the test positivity confirmed in a reference laboratory. In this study, 104 subjects with high-risk aPL profile (positive lupus anticoagulant, anticardiolipin, and anti-β₂–glycoprotein I antibodies, triple positivity) confirmed in a reference laboratory, were followed up for a mean of 4.5 years. There were 25 first TEs (5.3% per year): the cumulative incidence after 10 years was 37.1% (95% confidence interval [CI], 19.9%-54.3%). On multivariate analysis, male sex (hazard ratio = 4.4; 95% CI, 1.5-13.1, P = .007) and risk factors for venous thromboembolism (hazard ratio = 3.3; 95% CI, 1.3-8.5, P = .01) were independent predictors for TEs. Aspirin did not significantly affect the incidence of TE. In conclusion, the occurrence of a first TE in carriers of high-risk aPL profile is considerable; it is more frequent among male subjects and in the presence of additional risk factors for venous TE. These data can help in the decision to initiate primary thromboprophylaxis in these subjects.

Summary: In some patients with previous venous thromboembolism (VTE) D-dimer levels (D-Dimer) tend to increase after oral anticoagulant therapy (OAT) is stopped. The aim of our study was to evaluate the predictive value of D-Dimer for the risk of VTE recurrence after OAT withdrawal. After a first episode of deep vein thrombosis (DVT) of the lower limbs and/or pulmonary embolism (PE), 396 patients (median age 67 years, 198 males) were followed from the day of OAT discontinuation for 21 months. D-dimer was measured on the day of OAT withdrawal (T1), 3-4 weeks (T2) and 3 months (+/− 10 days, T3) thereafter. The main outcome events of the study were: objectively documented recurrent DVT and/or PE. D-dimer was found to be increased in 15.5%, 40.3% and 46.2% of the patients at T1, T2 and T3, respectively. In 199 (50.2%) patients, D-dimer levels were elevated in at least one measurement. During a follow-up of 628.4 years, 40 recurrences were recorded (10.1% of patients; 6.4% patient-years of follow-up). D-dimer was increased in at least one measurement in 28 of these cases, but remained normal in 11 subjects (three of whom had recurrent events triggered by circumstantial factors, three with malignancyassociated factors) (in one subject D-dimer was not measured). The negative predictive value (NPV) of D-dimer was 95.6% (95% CI 91.6-98.1) at T3 and was even higher (96.7%; 95% CI 92.9-98.8) after exclusion of the six recurrences due to circumstantial factors. Only five idiopathic recurrences occurred in the 186 patients with consistently normal D-dimer. In conclusion, D-dimer has a high NPV for VTE recurrence when performed after OAT discontinuation.