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Sanchis-Gomar F.,University of Valencia | Lippi G.,Academic Hospital of Parma
Journal of Strength and Conditioning Research | Year: 2012

The World Antidoping Agency (WADA) has introduced some changes in the 2012 prohibited list. Among the leading innovations to the rules are that both 5-aminoimidazole-4-carboxamide-1-b-D-ribofuranoside (peroxisome proliferator-activated receptor-d [PPAR-d]-5' adenosine monophosphate-activated protein kinase [AMPK] agonist) and GW1516 (PPAR-d-agonist) are no longer categorized as gene doping substances in the new 2012 prohibited list but as metabolic modulators in the class "Hormone and metabolic modulators." This may also be valid for the angotensin II receptor blocker telmisartan. It has recently been shown that telmisartan might induce similar biochemical, biological, and metabolic changes (e.g., mitochondrial biogenesis and changes in skeletal muscle fiber type) as those reported for the former call of substances. We suspect that metabolic modulators abuse such as telmisartan might become a tangible threat in sports and should be thereby targeted as an important antidoping issue. The 2012 WADA prohibited list does not provide telmisartan for a potential doping drug, but arguments supporting the consideration to include them among "metabolic modulators" are at hand. © 2012 National Strength and Conditioning Association.

Favaloro E.J.,Institute of Clinical Pathology and Medical Research ICPMR | Lippi G.,Academic Hospital of Parma
Seminars in Thrombosis and Hemostasis | Year: 2015

A new generation of antithrombotic agents has recently emerged. These provide direct inhibition of either thrombin (factor IIa [FIIa]) or FXa, and are increasingly replacing the classical anticoagulants (heparin and coumarins such as warfarin) in clinical practice for a variety of conditions. These agents have been designated several acronyms, including NOACs, DOACs, and TSOACs, respectively, referring to new (novel; non-vitamin K antagonist) oral anticoagulants, direct oral anticoagulants, and target-specific oral anticoagulants, and currently include dabigatran (FIIa inhibitor), and rivaroxaban, apixaban, edoxaban, and betrixaban (FXa inhibitors). The pervading mantra that NOACs do not require laboratory monitoring is countered by ongoing recognition that laboratory testing for drug effects is needed in many situations. Moreover, since these agents do not require laboratory monitoring, some clinicians inappropriately take this to mean that they do not affect hemostasis tests. This review aims to briefly review the laboratory studies that have evaluated the NOACs against a wide range of laboratory assays to assess utility for qualitative or quantitative measurements of these drugs, as well as interferences that may cause misdiagnosis of hemostatic defects. Point of care testing, including use of alternate samples such as urine and serum, is also under development but is not covered extensively in this review. The main aims of this article are to provide practical guidance to general laboratory testing for NOACs, as well as to help avoid diagnostic errors associated with hemostasis testing performed on samples from treated patients, as these currently comprise major challenges to hemostasis laboratories in the era of the NOACs. © 2015 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York.

Lippi G.,Academic Hospital of Parma | Plebani M.,University of Padua
Clinical Chemistry and Laboratory Medicine | Year: 2012

Homocysteine is a sulfur-containing amino acid, which is synthesized from the precursor methionine through a multi-step process, and then reconverted to methionine or catabolyzed into cysteine. The presence of vitamin B9 (folic acid), vitamin B6 (pyridoxine) and vitamin B12 (cobalamin) is essential in homocysteine metabolism, wherein deficiency of one or more of these nutrients is associated with various degree of hyperhomocysteinemia. There is little doubt that hyperhomocysteinemia is associated with several human disorders, such as cardiovascular disease, neurodegenerative disorders, pregnancy complications and fractures, so that its measurement might be useful for risk assessment. Nevertheless, several randomized homocysteine-lowering therapy trials have failed to show that supplementation with vitamins B substantially modifies (and - more importantly - improves) the end points and the related outcomes. According to the current state of scientific knowledge, it seems thus reasonable to conclude that lowering homocysteine alone is probably insufficient to mitigate the risk of thromboembolic, cardiovascular and neurodegenerative disorders inasmuch as this bizarre amino acid acts in strict synergy with other probably more powerful risk factors. Several lines of evidence suggest, however, that its measurement may be helpful for identifying subjects at greater risk of disease, who may thus benefit from a more aggressive treatment of other modifiable risk factors, as recently shown by result of the 5-year Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial. Copyright © 2012 by Walter de Gruyter.

Lippi G.,Academic Hospital of Parma | Plebani M.,University of Padua
Clinical Chemistry and Laboratory Medicine | Year: 2012

Ethylenediaminetetra-acetic acid (EDTA) is widely used as anticoagulant in laboratory medicine. EDTA-dependent pseudothrombocytopenia is a rare phenomenon (i.e., around 0.1% in the general population), which is mostly due to the presence of EDTA-dependent antiplatelet antibodies that react optimally between 0°C and 4°C, recognize the cytoadhesive receptors gpIIb-IIIa, stimulate the expression of activation antigens, trigger activation of tyrosine kinase, platelet agglutination and clumping in vitro, which finally lead to a spuriously decreased platelet count. The reliable and timely identification of this artifact is essential, since there a high chance that it may be confused with other life-threatening platelet disorders, or otherwise lead to inappropriate clinical and therapeutic decision-making. Five basic criteria should be fulfilled to raise the clinical suspicion of EDTA-dependent pseudothrombocytopenia, i.e., (i) abnormal platelet count, typically< 100×109/L; (ii) occurrence of thrombocytopenia in EDTA-anticoagulated samples at room temperature, but to a much lesser extent in samples collected with other anticoagulants and/or kept warmed at ∼37°C; (iii) time-dependent fall of platelet count in the EDTA specimen; (iv) evidence of platelet aggregates and clumps in EDTA-anticoagulated samples with either automated cell counting or microscopic analysis; (v) lack of signs or symptoms of platelet disorders. Several remedies have been proposed, such as warming the sample to 37°C or using additives or specific formulations of anticoagulants including buffered sodium citrate, heparin, ammonium oxalate, β-hydroxyethyltheophylline, sodium fluoride, CPT (trisodium citrate, pyridoxal 5'-phosphate and Tris), antiplatelet agents, potassium azide, amikacin, kanamycin or other aminoglycosides, and calcium replacement with the simultaneous addition of calcium chloride/heparin. According to available evidences, the most suitable and practical approach so far for most clinical laboratories seems, however, the recollection of blood samples using sodium citrate, CPT or calcium chloride/heparin as additives, maintaining the specimen at 37°C until the platelet count has been completed. © 2012 by Walter de Gruyter • Berlin • Boston.

Lippi G.,U.O. Diagnostica Ematochimica | Cervellin G.,Academic Hospital of Parma
Critical Reviews in Clinical Laboratory Sciences | Year: 2014

The prognostic significance of cardiospecific troponins and natriuretic peptides in patients with myocardial ischemia is well established, and their measurement is now endorsed by the most important guidelines and recommendations for diagnosis and management of heart failure (HF). Additional biomarkers have also been investigated to support clinical judgment and diagnostic imaging in the stratification of risk of cardiac dysfunction in patients with myocardial infarction (MI). We have performed a systematic analysis of the current scientific literature regarding the most important biomarkers of HF, selecting all prospective studies with adequate sample size (i.e. >100 patients) that have assessed, during the early phase of myocardial ischemia, the prognostic value of emergent biomarkers for new-onset HF or deterioration of cardiac function in patients with MI. This analysis has provided some good evidence suggesting that, in most cases, the use of diagnostic biomarkers of cardiac dysfunction does not translate into efficient risk prediction of HF. However, some notable exceptions were found, including biomarkers of cardiac fibrosis (especially galectin-3), growth differentiation factor-15 (GDF-15), osteoprotegerin, C-reactive protein (CRP), and red blood cell distribution width (RDW). Nevertheless, future studies with well-defined characteristics including the use of larger sample sizes, standardized end points, and replication populations, along with benchmark analyses against other consolidated biomarkers (i.e. cardiospecific troponins and natriuretic peptides), should be planned. Such evaluations will help to establish whether an integrated approach including biomarkers of different pathogenetic pathways-for example, apoptosis, stress of cardiomyocytes, cardiac fibrosis, inflammation, and extra-cardiac involvement-may be cost effective for identifying patients at increased risk of developing HF, and who, therefore, may benefit from a tailored therapeutic strategy. © 2014 Informa Healthcare USA, Inc.

Lippi G.,Academic Hospital of Parma
European Journal of Internal Medicine | Year: 2013

A timely and efficient diagnosis is critical in patients with chest pain, to optimize the efficacy of myocardial revascularization in those with an acute coronary syndrome, and offset the increasing overcrowding in the emergency room by early discharge of subjects without myocardial ischemia. Although cardiospecific troponins remain the biochemical gold standards for diagnosing an acute coronary syndrome, several additional biomarkers have been proposed. As a general rule, there are important issues that should be addressed when combining an innovative diagnostic test with troponin, including a benchmark evaluation of diagnostic performance, the impact on throughput and turnaround time, along with the analytical features of the assay and the cost to benefit ratio of a multi-marker approach. Despite a considerable amount of data has been published, there is insufficient analytical and clinical evidence to support the use of most of these novel biomarkers as surrogates or in combination with troponin for diagnosing ischemic heart disease, especially when the latter is assessed with the novel highly-sensitive immunoassays. © 2012 European Federation of Internal Medicine.

Lippi G.,Academic Hospital of Parma | Favaloro E.J.,Westmead Hospital | Mattiuzzi C.,General Hospital of Trento
Seminars in Thrombosis and Hemostasis | Year: 2015

The recent development and marketing of novel direct oral anticoagulants (DOACs) represents a paradigm shift in the management of patients requiring long-term anticoagulation. The advantages of these compounds over traditional therapy with vitamin K antagonists include a reportedly lower risk of severe hemorrhages and the limited need for laboratory measurements. However, there are several scenarios in which testing should be applied. The potential for drug-to-drug interaction is one plausible but currently underrecognized indication for laboratory assessment of the anticoagulant effect of DOACs. In particular, substantial concern has been raised during Phase I studies regarding the potential interaction of these drugs with some antibiotics, especially those that interplay with permeability glycoprotein (P-gp) and cytochrome 3A4 (CYP3A4). A specific electronic search on clinical trials published so far confirms that clarithromycin and rifampicin significantly impair the bioavailability of dabigatran, whereas clarithromycin, erythromycin, fluconazole, and ketoconazole alter the metabolism of rivaroxaban in vivo. Because of their more recent development, no published data were found for apixaban and edoxaban, or for potential interactions of DOACs with other and widely used antibiotics. It is noteworthy, however, that an online resource based on Food and Drug Administration and social media information, reports several hemorrhagic and thrombotic events in patients simultaneously taking dabigatran and some commonly used antibiotics such as amoxicillin, cephalosporin, and metronidazole. According to these reports, the administration of antibiotics in patients undergoing therapy with DOACs would seem to require accurate evaluation as to whether dose adjustments (personalized or antibiotic class driven) of the anticoagulant drug may be advisable. This might be facilitated by direct laboratory assessments of their anticoagulant effect ex vivo © 2015 by Thieme Medical Publishers, Inc.

Lippi G.,Academic Hospital of Parma | Favaloro E.J.,Westmead Hospital
Clinical Chemistry and Laboratory Medicine | Year: 2015

A new generation of antithrombotic agents, which are conventionally known as direct oral anticoagulants (DOACs), have recently emerged and are continuing to be developed. These provide direct inhibition of either thrombin (factor IIa; FIIa) or activated factor X (FXa) and currently include dabigatran (FIIa inhibitor) and rivaroxaban, apixaban, and edoxaban (FXa inhibitors). The dogma that DOACs do not require laboratory monitoring is countered by ongoing recognition that laboratory testing for drug effects is needed in many situations. In this review, we summarize the background to establishment of DOACs, assess which tests were found to be useful to screen for or quantitate drug effects/levels, and then review published guidelines/recommendations to assess concordance. In brief, (a) for the anti-FIIa agent dabigatran, the recommended screening assays are activated partial thromboplastin time (APTT) and/or thrombin time (TT), and the quantitative assays (using a dabigatran standard) are dilute TT/direct thrombin inhibitor assay (Hemoclot thrombin inhibitor) or an ecarin-based assay such as the ecarin clot time (ECT); (b) for the anti-FXa agent rivaroxaban, the recommended screening assay is the prothrombin time (PT), but this was not endorsed by all guidelines, and the quantitative assay (using a specific rivaroxaban standard) is an anti-FXa assay; (c) for the anti-FXa agent apixaban, the general insensitivity of PT and APTT prevented most groups from providing recommendation, and instead there was generalized support for direct quantitative assessment using anti-FXa assays and specific apixaban standard; (d) there is insufficient data for other direct anti-FXa agents and limited guidance in the literature. © 2015 by De Gruyter 2015.

Adcock Funk D.M.,Esoterix Inc. | Lippi G.,Academic Hospital of Parma | Favaloro E.J.,Westmead Hospital
Seminars in Thrombosis and Hemostasis | Year: 2012

Samples for hemostasis testing drawn into sodium citrate anticoagulant are vulnerable to the effects of preanalytical variables associated with sample processing, transportation, and storage. These variables include the temperature at which samples are transported and stored; the stability of the samples once processed; whether maintained at room temperature, refrigerated, or frozen; methods of centrifugation; as well as the potential impact of using an automated line. Acknowledgment of these variables, as well as understanding their potential impact on assay results, is imperative to the reporting of high quality and accurate results. This article discusses the preanalytical issues associated with sample processing, transportation, and storage and also presents the ideal conditions for sample handling. © 2012 by Thieme Medical Publishers, Inc.

Cervellin G.,Academic Hospital of Parma | Lippi G.,Academic Hospital of Parma
Seminars in Thrombosis and Hemostasis | Year: 2014

The history of myocardial infarction (MI) diagnostics has gone through a continuous evolution over the past century, when several new discoveries have contributed to remarkably increase the number of patients appropriately diagnosed with this condition. The tale of MIs and Men displays rather a long history, since atherosclerosis was found to be present in humans several centuries before modern civilization and the identification of the most prevalent risk factors. It was only at the end of the 19th century and at the beginning of the 20th century that the physicians acknowledged that MI is principally sustained by coronary thrombosis, and that the clinical picture of MI could be subsequently confirmed at autopsy. With the first description of the electrocardiogram (ECG) in the 1910s and 1920s, the history of modern MI diagnostics really began. Additional important discoveries followed, which are mainly represented by radiography, echocardiography, computed tomography, and magnetic resonance imaging of the heart. Another major breakthrough occurred at the down of the third millennium, with the development of commercial immunoassays for the measurement of cardiac troponin I and T, which represent now the cornerstones for identifying any kind of myocardial injury, thus including MI. The major advancements in the understanding of MI pathophysiology and the progressive introduction of efficient diagnostic tools will be described and discussed in this narrative historical review. © 2014 by Thieme Medical Publishers, Inc.

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