Evaluating the clinical usefulness of platelet function testing: Considerations for the proper application and interpretation of performance measures

ArticleinThrombosis and Haemostasis 109(2) · December 2012with15 Reads
DOI: 10.1160/TH12-08-0608 · Source: PubMed
Various diagnostic and prognostic performance measures have been used to describe the clinical usefulness of platelet function testing in the evaluation and management of patients taking P2Y 12 inhibitors, which reduce the risk for thrombosis due to their action on the platelet P2Y 12 receptor. Platelet function tests are used to confirm the presence of an antiplatelet effect of a P2Y 12 inhibitor, and confirmation that the pharmacodynamic effect is associated with a reduction in the rate of thrombosis. Despite this clear association, enthusiasm for the clinical usefulness of platelet function testing has been tempered based on observed sensitivity, specificity, and positive predictive value for the detection of future thrombotic events. However, evaluating the prognostic utility of a test based on diagnostic performance indicators is not appropriate because prognostic tests are not used to diagnose which patients will have events; instead, they are used to assist in risk stratification. Therefore, when evaluating the usefulness of platelet function testing, diagnostic performance measures such as sensitivity, specificity, and predictive values should focus on diagnostic performance in identifying a pharmacodynamic effect, and prognostic performance should be evaluated using prognostic performance measures such as hazard ratios and net reclassification improvement, which are comparable to other well-established risk factors for cardiovascular events.
    • "There is an additional layer of complexity where the potential prognostic factor is one of several, and is linked to several outcomes, as was the case in this example. As discussed in Dahlen et al. [36] , it is not sufficient to demonstrate that there is a statistically significant association between a test result and a given outcome, as this may not be clinically useful. Adjusted results show the incremental value of adding a (new) prognostic factor to existing ones for predicting an individual's future risk [37]. "
    [Show abstract] [Hide abstract] ABSTRACT: Prognostic factors are associated with the risk of future health outcomes in individuals with a particular health condition. The prognostic ability of such factors is increasingly being assessed in both primary research and systematic reviews. Systematic review methodology in this area is continuing to evolve, reflected in variable approaches to key methodological aspects. The aim of this article was to (i) explore and compare the methodology of systematic reviews of prognostic factors undertaken for the same clinical question, (ii) to discuss implications for review findings, and (iii) to present recommendations on what might be considered to be 'good practice' approaches. The sample was comprised of eight systematic reviews addressing the same clinical question, namely whether 'aspirin resistance' (a potential prognostic factor) has prognostic utility relative to future vascular events in patients on aspirin therapy for secondary prevention. A detailed comparison of methods around study identification, study selection, quality assessment, approaches to analysis, and reporting of findings was undertaken and the implications discussed. These were summarised into key considerations that may be transferable to future systematic reviews of prognostic factors. Across systematic reviews addressing the same clinical question, there were considerable differences in the numbers of studies identified and overlap between included studies, which could only partially be explained by different study eligibility criteria. Incomplete reporting and differences in terminology within primary studies hampered study identification and selection process across reviews. Quality assessment was highly variable and only one systematic review considered a checklist for studies of prognostic questions. There was inconsistency between reviews in approaches towards analysis, synthesis, addressing heterogeneity and reporting of results. Different methodological approaches may ultimately affect the findings and interpretation of systematic reviews of prognostic research, with implications for clinical decision-making.Systematic review registration: This review of systematic reviews in one medical area has been used to generate a number of recommendations for those undertaking systematic reviews of prognostic research; these include a step-wise hierarchical approach to study selection and suggested approaches for analysis (e.g. maximisation of data for meta-analysis). This work adds to and extends the growing body of methodological evidence in this field.
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    • "The main issue with these reagents is the elevated risk of adverse bleeding, due to the therapeutics targeting molecular pathways that are important for both thrombotic processes and normal hemostasis.90 This issue is compounded because the assessment of bleeding risk in patients receiving one or more of these therapies is complicated,91,92 generally requiring specialized platelet function analysis where the relationship between platelet function testing and bleeding in different patient groups on combinational therapy is not clear, due to limited data. "
    [Show abstract] [Hide abstract] ABSTRACT: While platelet activation is essential to maintain blood vessel patency and minimize loss of blood upon injury, untimely or excessive activity can lead to unwanted platelet activation and aggregation. Resultant thrombosis has the potential to block blood vessels, causing myocardial infarction or stroke. To tackle this major cause of mortality, clinical therapies that target platelet responsiveness (antiplatelet therapy) can successfully reduce cardiovascular events, especially in people at higher risk; however, all current antiplatelet therapies carry an increased probability of bleeding. This review will evaluate new and emerging targets for antithrombotics, focusing particularly on platelet glycoprotein VI, as blockade or depletion of this platelet-specific receptor conveys benefits in experimental models of thrombosis and thromboinflammation without causing major bleeding complications.
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    • "Flow cytometry allows the analysis of individual platelet functional capability and the measurement of the expression of platelet activation markers on individual platelets as well as the quantitation of associates between platelets and other blood cells. The most common platelet activation markers assessed by flow cytometry are P-selectin expression on the platelet surface (as a marker of í µí»¼-granule secretion), the conformational change of GP IIb/IIIa into its active state (measured with monoclonal antibody PAC-1), platelet-leukocyte conjugates, microparticle examination, exposure of anionic, negatively charged phospholipids on the platelet surface (procoagulant activity), and phosphorylation of vasodilatorstimulated phosphoprotein-phosphorylation (VASP-P) (BioCytex, Marseille, France), as a marker of P2Y12 receptor activation-dependent signaling181920. Many laboratories have measured a variety of different platelet activation markers and shown that they are elevated in various clinical conditions such as unstable angina, acute myocardial infarction, preeclampsia, peripheral vascular disease, and cerebrovascular ischemia. "
    [Show abstract] [Hide abstract] ABSTRACT: The major goal of traditional platelet function tests has been to screen and diagnose patients who present with bleeding problems. However, as the central role of platelets implicated in the etiology of arterial thrombotic diseases such as myocardial infarction and stroke became widely known, platelet function tests are now being promoted to monitor the efficacy of antiplatelet drugs and also to potentially identify patients at increased risk of thrombosis. Beyond hemostasis and thrombosis, an increasing number of studies indicate that platelets play an integral role in intercellular communication, are mediators of inflammation, and have immunomodulatory activity. As new potential biomarkers and technologies arrive at the horizon, platelet functions testing appears to take on a new aspect. This review article discusses currently available clinical application of platelet function tests, placing emphasis on essential characteristics.
    Full-text · Article · May 2014
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