D-Dimer for venous thromboembolism diagnosis: 20 years later

Summary.  Twenty years after its first use in the diagnostic workup of suspected venous thromboembolism (VTE), fibrin D-dimer (DD) testing has gained wide acceptance for ruling out this disease. The test is particularly useful in the outpatient population referred to the emergency department because of suspected deep vein thrombosis (DVT) or pulmonary embolism (PE), in which the ruling out capacity concerns every third patient clinically suspected of having the disease. This usefulness is based on the high sensitivity of the test to the presence of VTE, at least for some assays. Due to its poor specificity precluding its use for ruling in VTE, DD testing must be integrated in comprehensive, sequential diagnostic strategies that include clinical probability assessment and imaging techniques such as lower limb venous compression ultrasonography for suspected DVT or multi-slice helical computed tomography for suspected PE. The present narrative review updates the data available on the use of the various commercially available DD assays in the diagnostic approach of clinically suspected VTE in distinct patient populations or situations, including outpatients and inpatients, patients with cancer, older age, pregnancy, a suspected recurrent event, limited thrombus burden, and patients already on anticoagulant treatment.     

A survey of adherence to haemophilia therapy in six European countries: results and recommendations

Summary. Very few studies have addressed the question of adherence of haemophiliacs to their treatment. The aim of our study was to compare their levels of adherence to therapy and also to provide recommendations. Professionals of an international research company performed individual interviews with 30 patients in each of six European countries (France, Germany, Italy, Spain, Sweden and UK) resulting in a total of 180 patients. Twenty‐eight interviews with haemophilia physicians and specialist nurses were also undertaken. Overall adherence to treatment was high (80–87% in each country). There was a positive correlation between greater adherence and younger age, prophylactic treatment, time spent with a haemophilia treatment centre (HTC) and the quality of the relationship with the haematologist and nurse. The four leading reasons for not using the prescribed amount of clotting factor or skipping the administration interval were reduction, fluctuation or disappearance of symptoms, forgetfulness, lack of time for treatment and convenience. These reasons differed according to the country and the age of the patient. The main suggestions made by patients to improve adherence related to HTC, environment and factor concentrates. Patients considered also that internet and electronic patient diaries were likely to improve adherence. In this selected group of European haemophilia patients, adherence to treatment appears higher than for most patients with other chronic diseases. However, it remains important to be aware of the possibility of non‐adherence given the serious implications, particularly when considering a differently selected group of patients.     

Should prophylaxis be used in adolescent and adult patients with severe haemophilia? An European survey of practice and outcome data

A survey of 21 haemophilia doctors, throughout Europe, who care for a total of approximately 5000 patients with bleeding disorders addressing practice and opinions regarding prophylaxis in patients aged 16-24 years and adults aged over 50 years, is presented. The outcome of adolescent patients who reduced or stopped prophylaxis was recorded. Eighteen of 19 respondents would consider modification of established prophylaxis in the adolescent age group, principal considerations being avoidance of risks of further concentrate exposure, predicted poor compliance and treatment costs. The preferred age for modification was 16-20 years, but there was very little consensus on the particular prophylactic regime recommended. Approximately, half of a cohort of 218 patients with severe haemophilia successfully reduced or stopped prophylaxis when they reached adolescence. Only 26 of 92 (28%) of the patient cohort who stopped prophylaxis, required reintroduction of a prophylactic regime and 12 of 59 (20%) of those who reduced the intensity of prophylaxis had to reintroduce a more intensive regime. A majority of respondents would consider starting prophylaxis in those over 50 years. There was no consensus as to indications for this practice or the nature of the prophylaxis protocol. We conclude that there is an absence of consensus on the management of patients with severe haemophilia, as they pass through adolescence and young adulthood, and reach the age of 50. Aggregate outcome data suggest a significant proportion of patients in the 18-22 years age range may be able to reduce or stop prophylaxis. A substantial number of older patients are on prophylaxis.     

Biological effects of aspirin and clopidogrel in a randomized cross-over study in 96 healthy volunteers

BACKGROUND: Some data suggest that biological 'resistance' to aspirin or clopidogrel may influence clinical outcome. OBJECTIVE: The aim of this study was to evaluate the relationship between aspirin and clopidogrel responsiveness in healthy subjects. METHODS: Ninety-six healthy subjects were randomly assigned to receive a 1-week course of aspirin 100 mg day(-1) followed by a 1-week course of clopidogrel (300 mg on day 1, then 75 mg day(-1)), or the reverse sequence, separated by a 2-week wash-out period. The drug effects were assessed by means of serum TxB2 assay, platelet aggregation tests, and the PFA -100 and Ultegra RPFA -Verify Now methods. RESULTS: Only one subject had true aspirin resistance, defined as a serum TxB2 level > 80 pg microL(-1) at the end of aspirin administration and confirmed by platelet incubation with aspirin. PFA-100 values were normal in 29% of the subjects after aspirin intake, despite a drastic reduction in TxB2 production; these subjects were considered to have aspirin pseudo-resistance. Clopidogrel responsiveness was not related to aspirin pseudo-resistance. Selected polymorphisms of platelet receptor genes were not associated with either aspirin or clopidogrel responsiveness. CONCLUSIONS: In healthy subjects, true aspirin resistance is rare and aspirin pseudo-resistance is not related to clopidogrel responsiveness.     

Clinical predictors of dual aspirin and clopidogrel poor responsiveness in stable cardiovascular patients from the ADRIE study

Summary. Background: Poor response to both aspirin and clopidogrel (dual poor responsiveness [DPR]) is a major risk factor for recurrent ischemic events. Objectives: The aim of this study was to identify factors associated with DPR, defined with specific tests, and derive a predictive clinical score. Methods: We studied 771 consecutive stable cardiovascular patients treated with aspirin (n = 223), clopidogrel (n = 111), or both drugs (n = 437). Aspirin responsiveness was evaluated by serum thromboxane (Tx)B₂ assay, and clopidogrel responsiveness by calculating the platelet reactivity index (PRI) on the basis of the phosphorylation status of the vasodilator phosphoprotein. The analysis was focused on patients treated with both drugs, and on independent predictors of DPR. Results: Among patients on dual therapy, there was no relevant correlation between TxB₂ levels and PRI values (r = 0.11). Sixty‐seven patients (15.4%) had DPR. Diabetes [odds ratio (OR) 1.89, 95% confidence interval (CI) 1.06–3.39], high body weight (> 86 kg vs. < 77 kg, OR 4.74, 95% CI 2.49–9.73), low aspirin dose (75–81 mg vs. ≥ 160 mg, OR 0.12, 95% CI 0.09–0.93) and high C‐reactive protein (CRP) level (> 1.6 mg L^?1 vs. < 0.6 mg L^?1, OR 3.66, 95% CI 1.74–8.72) were independently associated with DPR, via increased TxB₂ levels, increased PRI, or both. These associations with TxB₂ and PRI were reproduced across the whole population. With use of a factor‐weighed score (c‐index = 0.74), the predicted prevalence of DPR was 57% in the highest strata of the score as compared with < 4% for the lowest strata. Conclusions: Diabetes, body weight, the aspirin dose and CRP levels are readily available independent predictors of DPR, and some are potential targets for reducing its prevalence.