Multiplate is another test. These tests are interesting, but I think they all have issues, whether your single agonist—in traditional platelet function, you do EC50, so you are looking at multiple variables and multiple concentrations. I think there are so many factors. To summarize, I am not a fan of those tests, and although they have been modified to look at platelet function, I think they still have issues, and I would appreciate everybody else’s perspective on this, but that is my opinion on using them for platelet function testing.
DR. SCHNEIDER: Because of your clinical practice, I would be interested in your comments on the use of TEG as a guide to replacement therapy in a patient who is bleeding, particularly after a procedure? Do you see a utility there?
DR. LEVY: Totally. I previously was at Emory and worked with Andreas Grunzig, and worked in the era of the stents. In that scenario, I agree. In a bleeding ECMO patient, I follow the tissue-factor viscoelastometry test, what is called the EXTEM Assay (TEM Systems Inc., Durham, NC) because to me, that’s the physiologic and pathophysiologic activation epitope.
In that scenario, I think it’s helpful. The bottom line is, if you’re clotting and you have normal whole-blood clot function that looks at all the factors of whole blood—and if you are bleeding, it means you have got a hole, a vascular defect, or there is something else I need to be looking for.
I think it’s a great test in that scenario, and I know you all are quite familiar with the whole concept of massive transfusion coagulopathy, and the studies that have looked at varying degrees of plasma to red cells, and all those scenarios. The reality is that the move now is, let’s use TEG and ROTEM to determine if we have adequately repleted factors with massive hemorrhage.
Part of the problem is that fibrinogen gets lost in the equation. So, to answer your question, I think it’s great in that scenario—with massive bleeding, with trauma, even with ventricular-assist devices, because you can have an international normalized ratio of 3 to 3.5, and you can still be clotting off due to other factors that cause hypercoagulability.
In that scenario, I think it’s a helpful test, but I prefer the ROTEM, because there is the tissue factor assay. In general, people using TEG use kaolin, which is such a nonspecific activator of platelets, and I think a lot has to do with the activator, but I think in that scenario, it has important applications.
DR. JENNINGS: This has been a great discussion for the clinical cardiologist and healthcare practitioners. I am interested to hear from each of you, where you think platelet function testing has its role currently, and if you have any types of recommendations as to when it may be informative in terms of evaluating your patients, or for patient outcomes, and where you think it may still fall into the realm of research—if you would still put it in the research arena.
I think it would be helpful to conclude with your bottom line, in terms of how you use platelet function testing, or when you use it for your patients.
DR. ANGIOLILLO: At our center, we do a lot of platelet function testing, but we do it in the context of research, not necessarily for clinical decision-making. This is largely based on the fact that, to date, most trials have been largely negative.
The first and only prospective randomized study to meet the primary end-point was the TROPICAL-ACS trial,9 which implements a concept of guided de-escalation therapy—going from a more potent to a less potent P2Y12 inhibitor, without having an increase in ischemic events. There was a trend toward a reduction in bleeding, but it did not reach statistical significance. As a concept, it is very interesting, and I think the study finally identified the right patient population to test this in.
The problem becomes, it is not that practical because to see a response to a given drug, the patient needs to be on the drug, and so the trial did imply de-escalating, but also escalating, in nearly 40% of patients. It is a starting point that we can build upon, with more trials to come. This is one setting. I think another setting is defining time-to-surgery in a patient on a P2Y12 inhibitor.
DR. LEVY: I agree. I think it is especially helpful in the patient who is on clopidogrel—maybe even prasugrel—and there is a concern about when to go for surgery because of the variability of effectiveness and resistance, etc. I think that is where it is effective.
Where I think we need significant additional work is the patient who has been on one of these agents, who has bled, who is a bit factor-depleted, thrombocytopenic, and you are concerned whether you still have an effect or not.
Yet these tests are dependent on certain things like hematocrit. They are dependent on some of the whole-blood tests, in particular. They are dependent on platelet number and, therefore, can be quirky and not informative when you have a critically bleeding patient.
So, in the maintenance phase and in the waiting-for-surgery phase, yes, I think they have a role. Where they really need additional development is in the patient who is bleeding, and the ability to measure platelet function is something that we really lack and needs additional investigation, in my opinion.
If a patient comes in with ACS, and has gotten into some trouble and they have bled, and you are resuscitating, that is where it is very helpful to have an idea of how much the platelets are contributing. Even though you do an EXTEM, you get a whole-blood clot, but it is still very much driven by fibrinogen. So again, critical bleeds in factor-depleted patients, we need to have a better assay that helps us understand.
DR. SCHNEIDER: I absolutely think that looking at recovery of platelet function can be used as a guide to when it is safer to do an invasive procedure. In our institution, we are using testing to target replacement, rather than throwing the kitchen-sink at patients. I think that this is where the strongest evidence in support of testing exists.
I firmly believe that we need to get, someday, to an evidence-based support for using individualized therapy. Sadly, I agree with Dominick that we are not there yet, and I think we should continue our efforts to refine the assays, as we have talked about a variety of ways to do that during our conversation today, and keep working on this issue from that perspective.
I also think, in development of antiplatelet agents, and looking for antiplatelet effects of other anticoagulants, the testing is pivotal. A lot of what Dominick does is what I do, as well, and so I think it is valuable in early-phase trials, and even Phase 4 trials, as we are trying to refine treatment.
For an average patient going to the catheterization lab, I agree with Dominick, we are not using platelet function testing to guide our therapy today, because of the failure of the trials that we have.
DR. JENNINGS: This exchange has been great. I think that we have had a very meaningful discussion and your discussion points are all terrific. It certainly does reflect where we are in the art of platelet function testing. To conclude, I think we all agree that platelet function testing is relevant for both assessment of thrombosis risk and for bleeding risk.
We need to continue to strive for evidence-based support. We all recognize its importance for early-phase trials, research and development, for looking at mechanisms of action, and of combination therapies. We have identified some ways that we might improve the assessment of platelet function, that tailoring treatment based on a single-agonist test may not be sufficient. There are attributes and deficiencies associated with these different tests.
We continue to work toward improved testing and improved assessment for looking at ways of improving patient outcomes. One thing we did not touch on due to time limitations is that there are obviously patient comorbidities—e.g., diabetes—and certain other factors can contribute to the assay results, and confound test interpretations.
It takes a lot of focus, a lot of work, and a lot of discussion such as what we have had today to move the field forward, and to improve our assessment of patients, and their risk for either thrombosis or bleeding.
Thanks so much to all of you for serving as faculty. I hope those who will be reading this and participating with us in our comments will find this to be useful, and encourage more discussion among us all, in terms of how to enhance platelet function testing for the improvement of clinical outcomes.