Antiplatelet agents including aspirin, clopidogrel and ticagrelor consistently rank as some of the most used medications in the United States and are becoming more prevalent throughout the rest of the world; it is estimated that over 30% of Americans over the age of 40 take aspirin daily and clopidogrel remains one of the top 50 prescriptions in the country with over 20 millions scripts written per year [1-3]. While conventional anticoagulants (warfarin, heparin) can be directly monitored through classic coagulation studies including PT and PTT, antiplatelet agents including aspirin, clopidogrel and ticagrelor are much less easy to identify in both presence and degree of efficacy. One of the most crucial clinical areas where associated risks must be taken into consideration and adverse events managed with these medications are scenarios of clinically significant bleeding, traumatic or spontaneous. In particular, the increasing average age of traumatic brain injuries (TBI) with associated hemorrhagic conversion or worsened outcomes due to increased anticoagulation and antiplatelet therapy (APT) has led to these medications becoming a ready target for identifying areas for intervention in the acutely ill patient [4-6].
Although platelet function assays (PFAs) have been in existence since the 1960s, the traditional, gold standard method of light aggregometry is slow and not a functional diagnostic tool in clinical scenarios where real-time information is of the essence to change outcomes . Although gross platelet dysfunction in terms of clot formation can be rapidly detected from more commonly available thromboelastographic modalities including TEG and ROTEM, these assays cannot discern if the issue is purely related to volume deficiency, intrinsic platelet abnormalities or is pharmacotherapy-induced. Development of methods to identify relative alterations specific to aspirin or P2Y12-receptor inhibitors have been developed and are now much more readily available. Unclear as of yet, however, is their clinical impact on patient care and outcomes. There are three primary systems available in the US: TEG-PM, VerifyNow and Multiplate Aggregometry. The table below lists interpretation values and some commentary on specific characteristics of each modality [6-8].
There are three primary systems available in the US: TEG-PM, (platelet mapping), VerifyNow (most widely available, reports platelet functions in terms of aspirin-reaction units (ARU) or P2Y12 reaction units (PRU)) and Multiplate Aggregometry. The table below lists interpretation values and some commentary on specific characteristics of each modality [6-8]. (most similar to the original light transmission aggregometry testing and therefore considered more intrinsically accurate than the other two).
Early prospective observational studies noted that all three modalities were able to successfully identify the presence of antiplatelet agents in patients with known antiplatelet therapy (APT) compliance . However, the authors do note that the TEG-PM does not have a designated manufacturer set point for identification of APT and, perhaps more noteworthy, the manufacturer-prescribed set point for the identification of salicylic-acid induced platelet dysfunction by the VerifyNow system was substantially overestimated (sensitivity 58%, specificity 89%). These limitations imply that there is significant room for interpretation error when using these test results in real time to make clinical decisions. As with any situation in medicine, we must weigh best practice in terms of risks and benefits to the patient—does the identification of APT-induced platelet dysfunction change clinical outcomes?
Does ensuring normal platelet function help our patients?
Based on previous research, the presence of thrombocytopenia (<175,000) or coagulopathy in trauma patients, especially in patients with ICH, was reported as being a significant predictor for progression of hemorrhage, increased post-injury morbidity and at a threshold of <100,000, a nine-fold increase in the risk of death from the insult [9-10]. Initial retrospective studies (2011) reported an improved survival rate in patients receiving platelets compared to plasma in massive resuscitation efforts when their injuries included a TBI [4,11,12]. This study had significant limitations, in that it did not include many more nuanced patient subgroups, including those who did not require massive transfusion resuscitation, those on antiplatelet therapy and those with spontaneous ICH. In an evaluation of patients with only mild or moderate coagulopathy or bleeding diatheses, transfusion of platelets was not correlated with any statistically significant change in functional outcome, and transfusion of FFP was correlated significantly with a worse functional outcome [4,13]. In 2016, the PATCH investigators released results of their multilevel assessment of outcomes using platelet transfusion in addition to standard care for patients on APT with spontaneous head bleeds. In a surprising turn from initial predictions (the AHA had preemptively recommended platelet transfusion as an experimental therapy for treatment of acute hemorrhagic stroke in this patient population in 2010), those randomized to receive platelet transfusions empirically with the assumption of decreased platelet function due to their home medications had a significantly increased risk of death or severe loss of independence three months after the event compared to those receiving standard care alone (OR 2.05, p=0.01) . Since this publication, there has continued to be conflicting evidence of varying benefits of platelet transfusion in patients with demonstrated platelet inhibition secondary to APTs [15-17]. Based on this, an empiric platelet transfusion for all patients on APT is not recommended at this time.
So it’s probably not for everyone--could we instead use these tests to guide resuscitations in select patients?
Unfortunately, the answer appears to be probably not. Maas et. al. performed a prospective observational study in patients presenting with ICH which included patients currently on APT and those with definitively no history of such to evaluate if PFA-indicated platelet dysfunction or history of APT were clinically correlated to hemorrhage progression or poorer functional outcomes. In 278 participants, both hematoma progression and poor functional outcomes were more closely associated with a history of antiplatelet therapy than PFA measures of platelet inhibition or dysfunction. Moreover, their analysis is notable for reproducing a concerning finding regarding PFAs: nearly 40% of patients measured at a limited or inhibited platelet function without any history of APT, making the reliability of these assays when used with manufacturing standards of norms suspect . Additional studies have shown that even in patients with a known history of APT, it can be estimated that approximately 20% are resistant and do not demonstrate effective inhibition by PFAs while another 16% of patients with demonstrated platelet inhibition are likely to have a nil or minimal functional response to platelet transfusion .
There continues to be ongoing research in this field to determine the best clinical use for these assays, and it is possible that in the future a real-time, point-of-care assessment of platelet dysfunction related to APT will be more beneficial than a thorough medication history. In the meantime, however, the use of these tests in emergency department or critical care treatment algorithms for trauma and intracranial hemorrhage continues to be institution-dependent.
Authored by Olivia Urbanowicz, MD
Dr. Urbanowicz is a rising PGY-2 in Emergency Medicine at the University of Cincinnati
Peer Review and Post by Ryan LaFollette, MD
Dr. LaFollette is an Assistant Program Director of Emergency Medicine at the University of Cincinnati
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