P. de Moerloose

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.

The association between circulating antibodies against domain I of beta2-glycoprotein I and thrombosis: an international multicenter study

Summary.  Background: Diagnosis of the antiphospholipid syndrome (APS) is difficult as a result of limited specificity of existing assays for detecting clinically relevant antiphospholipid antibodies. Anti‐beta2‐glycoprotein I (beta2GPI) antibodies play a central role in the disease process of APS. Objectives: We have investigated the relation between antiphospholipid antibodies with specificity for domain I of beta2GPI and thrombosis/pregnancy morbidity in an international multicenter study. Patients/methods: Four hundred and seventy‐seven patients derived from nine different centres met the inclusion criterion of having anti‐beta2GPI antibodies in their plasma/serum. Clinical data and results of tests for lupus anticoagulant, anti‐cardiolipin antibodies and anti‐beta2GPI antibodies were established at the different centres of inclusion. After being re‐tested for the presence of IgG and/or IgM anti‐beta2GPI antibodies, the samples were tested for the presence of IgG‐directed against domain I of beta2GPI and results were correlated with the thrombotic and obstetric history. Results: Re‐testing for the presence of anti‐beta2GPI antibodies resulted in inclusion of 442/477 patients. IgG class anti‐domain I antibodies were present in plasma of 243/442 patients (55%). 201/243 (83%) had a history of thrombosis. This resulted in an odds ratio of 3.5 (2.3–5.4, 95% confidence interval) for thrombosis. Anti‐domain I IgG antibodies were also significantly correlated with obstetric complications [odds ratio: 2.4 (1.4–4.3, 95% confidence interval)]. Conclusion: In this multicenter study, the detection of IgG antibodies that are directed against domain I of beta2GPI proved to be more strongly associated with thrombosis and obstetric complications than those detected using the standard anti‐beta2GPI antibody assay.

Influence of CYP2C19 and CYP3A4 gene polymorphisms on clopidogrel responsiveness in healthy subjects

P . FONTANA,* J . S . HULOT , P . DE MOERLOOS E* and P . GAUSSEM *Division of Angiology and Haemostasis, Department of Internal Medicine, Faculty of Medicine and University Hospitals of Geneva, Geneva, Switzerland; AP-HP, Hôpital Pitié-Salpêtrière, Service de Pharmacologie, Unité de Pharmacogénétique, Université Pierre et Marie Curie-Paris6, UMR S 621 (INSERM), Paris; and AP-HP, Hôpital Européen Georges Pompidou, Service d Hématologie Biologique, INSERM Unité 765, Université Paris-Descartes, Paris, France

Proposals for the measurement of anti-β2-glycoprotein I antibodies. Standardization Group of the European Forum on Antiphospholipid Antibodies

Derenne JP. Obstructive sleep apnea and venous thromboembolism. JAMA 2002; 287: 2655–6. 4 Fowkes FJI, Price JF, Fowkes FGR. Incidence of diagnosed deep vein thrombosis in the general population: systematic review. Eur J Vasc Endovasc Surg 2003; 25: 1–5. 5 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O’Fallon WM, Melton LJ 3rd. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158: 585–93.

Use of the PFA-100 closure time to predict cardiovascular events in aspirin-treated cardiovascular patients: a systematic review and meta-analysis

Summary.  Background: PFA‐100™ is a point‐of‐care assay that evaluates platelet reactivity in high‐shear‐stress conditions by measuring the closure time (CT) of a membrane aperture. When determined with a collagen/epinephrine cartridge (CEPI), the CT is usually prolonged by aspirin. Studies of the predictive value of a short PFA‐100™CTCEPI for ischemic events in aspirin‐treated patients have given variable results. Objectives: To conduct a systematic review and meta‐analysis of studies on the clinical predictive value of a short PFA‐100™CTCEPI in aspirin‐treated cardiovascular patients. Patients and methods: Relevant studies were identified by scanning electronic databases. Studies were selected if they included aspirin‐treated patients with symptomatic atherosclerosis, measured the PFA‐100™CTCEPI, used a CT cut‐off value to define aspirin ‘responders’ and ‘non‐responders’, and reported ischemic events. Results: We selected seven non‐prospective studies (1466 patients) and eight prospective studies (1227 patients). In non‐prospective studies, the PFA‐100™CTCEPI was performed after the ischemic clinical endpoint, and a publication bias was identified. In prospective studies, the global odds ratio (OR) for the recurrence of an ischemic event in ‘aspirin non‐responders’ relative to ‘aspirin responders’ was 2.1 [95% confidence interval (CI) 1.4–3.4, P < 0.001]. Pooled analysis with a random effect model revealed no heterogeneity (Q Cochran P = 0.36 and I2 = 9.4%). Conclusions: A short PFA‐100™CTCEPI is associated with increased recurrence of ischemic events in aspirin‐treated cardiovascular patients. This finding needs to be confirmed in stable ischemic patients, and the PFA‐100™CTCEPI cut‐off needs to be refined in these patients.

Contribution of noninvasive evaluation to the diagnosis of pulmonary embolism in hospitalized patients

The effectiveness of new diagnostic tools for suspected pulmonary embolism (PE), such as clinical probability assessment, plasma D-dimer (DD) measurement and lower limb venous compression ultrasonography (US), has not been specifically studied in patients with a suspected PE occurring during hospital stay. This study applied a sequential, decision analysis-based strategy adding these instruments to a ventilation/perfusion lung scan in a cohort of 114 consecutive inpatients clinically suspected of PE in order to establish in how many patients a pulmonary angiogram could thereby be avoided. A definitive diagnosis could be established by the noninvasive protocol in 61% of these patients: normal/near-normal lung scan, 14%; high probability lung scan, 19%; clinical probability combined with lung scan result, 18%; and US, 8%. Specificity of DD was only 7% and contributed to the exclusion of PE in only two patients. Pulmonary angiography was required in 39% of patients. The 3-month thromboembolic risk in patients in whom PE was excluded by the diagnostic process was 0% (95% confidence interval 0-4.9%). In conclusion, a noninvasive work-up for suspected pulmonary embolism is effective in hospitalized patients, allowing to forego angiography in 61% of them, and it appears to be safe, although this should be further investigated. In contrast to outpatients, D-dimer measurement appears to be useless in hospitalized patients.

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.

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

Summary.  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 μL−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.

Replacement therapy for invasive procedures in patients with haemophilia: literature review, European survey and recommendations.

Summary.  Although most surgical and invasive procedures can be performed safely in patients with haemophilia, the optimal level and duration of replacement therapy required to prevent bleeding complications have not been established conclusively. For providing more insight into optimal therapy during invasive procedures, a literature review of surgical procedures in patients with haemophilia was conducted. Concomitantly, current practice was surveyed in 26 European Haemophilia Comprehensive Care Centres, representing 15 different countries. The review identified 110 original papers published between 1965 and 2007. Of these, only two studies were randomized controlled trials. Target levels and the duration of replacement therapy in the published studies were as follows. For major orthopaedic surgery: preoperative targets were 80–90%; postoperative targets showed a high degree of variation, with trough levels ranging from 20% to 80%, duration 10–14 days; for liver biopsy, 70–100%, 1–7 days; tonsillectomy: 90–100%, 5–11 days; indwelling venous access device insertion: 100%, 3–10 days; circumcision: 50–60%, 2–4 days; dental surgery: 30–50%, single treatment. With the exception of dental surgery, current practice in Europe, as assessed by the survey, was largely in agreement with published data. In conclusion, this study provides both a comprehensive review and a large survey of replacement therapy in patients with haemophilia undergoing invasive procedures; these data have informed the consensus practical treatment recommendations made in this paper. This study highlights the need for better‐designed studies in order to better define minimal haemostatic levels of replacement therapy and optimal treatment duration.

D‐dimer levels during delivery and the postpartum

Summary.  Background: D‐dimer (DD) measurement has proved to be very useful to exclude venous thromboembolism (VTE) in outpatients. However, during pregnancy, the progressive increase as well as the interindividual variations of DD means that in this instance they are of poor value to rule out VTE. Only a few studies have reported measurements of DD levels in the postpartum. Objectives: To measure DD sequentially in the puerperium in order to determine when DD levels return to values obtained in non‐pregnant women and can again be used in the exclusion of VTE. Patients and methods: After uncomplicated pregnancies, 150 women delivering at term either vaginally (n = 100) or by cesarean section (n = 50) were included. DD levels were measured immediately following delivery and next at days 1, 3, 10, 30 and 45. Results: There was a marked elevation of DD at delivery, especially when instrumental. All DD measurements were above 500 ng mL−1 at delivery, at day 1 and at day 3 postpartum. A sharp decrease in DD was observed between day 1 and day 3, followed by a slight increase at day 10. At day 30 and day 45, respectively, 79% and 93% of women in the vaginal delivery group and 70% and 83% in the cesarean group had levels below 500 ng mL−1. Bleeding, breastfeeding and heparin prophylaxis did not modify DD levels significantly. Conclusion: Using the Vidas DD new assay, our study provides reference intervals for DD in the postpartum period. Using a cut‐off at 500 ng mL−1, DD measurement for ruling out VTE was found to be useful again 4 weeks after delivery.