Antiplatelet drug 'resistance'. Part 2: laboratory resistance to antiplatelet drugs-fact or artifact?

In the second part of their Review on resistance to antiplatelet medication, the authors discuss the various laboratory tests of platelet function and highlight the limitations of these methods for determining the true thrombotic status of the patient. Many patients experience recurrent ischemic events despite optimal antiplatelet therapy. This has generated much interest in finding a laboratory test of platelet function to identify such patients, who have been termed 'nonresponders' or antiplatelet 'resistant'. Laboratory tests of platelet function have identified 'resistance' in 5–60% of patients taking aspirin and 4–30% of those taking clopidogrel. However, these tests of 'resistance' have not correlated closely with subsequent recurrent events, and have not reliably identified nonresponders to antiplatelet therapy. Here, we identify and discuss three major limitations common to all these tests. Firstly, they are performed on citrate-anticoagulated blood, secondly, blood is stored for a variable period of time, and thirdly, the assessment of thrombotic status on the basis of platelet response to only one or two agonists ignores the complexity of the mechanism of platelet thrombus formation in vivo . In this Review we discuss the significance of these important limitations, and the applicability of such in vitro platelet function tests to the prediction of in vivo events. We conclude that such tests are so unphysiological that they cannot reliably predict the true thrombotic status of patients. Identification of 'resistance' on the basis of these tests lacks sensitivity and specificity for identifying thrombotic risk, and is likely to be artifactual. Key Points We believe that the true thrombotic status of patients cannot be assessed using currently available in vitro tests and, therefore, the existence of 'resistance' to antiplatelet therapy is questionable Most data on 'resistance' to antiplatelet drugs are provided by platelet aggregometry, modified thromboelastography, the platelet function analyzer 100 (PFA-100) ® a and VerifyNow ® b assays With the exception of thrombin, physiological platelet stimuli do not cause secondary aggregation, granule release and thromboxane A 2 generation in native blood The use of citrated blood with critically low Ca 2+ distorts the in vivo effect of platelet agonists and antagonists None of the currently available in vitro tests of platelet function allow the assessment of thrombin generation by activated platelets a