In patients with coronary artery disease (CAD), a high blood level of immature platelets is associated with elevated risk of future adverse events, according to findings that will be published in the November 18/25, 2014, issue of the Journal of the American College of Cardiology.

If future studies confirm the validity of this biomarker for risk stratification, it may eventually be used to individualize antiplatelet therapy, the authors say.

At a median follow-up of 31 months, 33.7% of patients had experienced a major adverse event: 10 died, 11 had an NSTEMI, 7 were hospitalized for chest pain, and 6 underwent unplanned revascularization. There were no differences in baseline characteristics between patients who did or did not experience an event. However, rates of MACE, death, and NSTEMI were higher for the top tertile of immature platelet count compared with the other tertiles (table 1).

Time-dependent ROC analysis identified 7,632 immature platelets/µL as an optimal cutoff point for predicting MACE, with a sensitivity of 70.7% and a specificity of 82.1%. After adjustment for age, admission diagnosis, index revascularization, heart failure, smoking, hematocrit, and baseline platelet count, patients with an immature platelet count above the cutoff point had a more than 4-fold higher risk of MACE (HR 4.65; 95% CI 1.78-12.16).

There was only a modest correlation between immature and overall platelet count.

A Path to Personalized Antiplatelet Therapy?

According to the investigators, the association between immature platelets and thromboembolic events likely reflects the larger size and hyperactivity of this platelet population. This hypothesis is supported by observations of a relationship between immature platelets and high residual reactivity in patients on DAPT, they add. However, they observe, since platelet count is elevated in the acute phase of an event, increased immature platelet count may also simply be a marker of systemic inflammatory activity.

Several studies have linked high residual platelet reactivity in patients receiving DAPT after DES implantation to increased risk of stent thrombosis, the researchers observe. Despite some setbacks from negative randomized trials, “antiplatelet therapy is shifting into a new paradigm of personalized therapy,” they say, and “[t]he current data offer a potential new and easily ascertained target for such a strategy.”

Dr. Kleiman and colleagues acknowledge that the study sample was small, limiting the number of variables examined to try to ensure that immature platelet count was in fact an independent predictor of adverse events. In addition, no data were available on the stability of immature platelet count over time, although such studies are underway. Finally, the paper provides no mechanistic explanation of the association between immature platelet count and clinical outcomes.

Not Ready for Prime Time

In an accompanying editorial, John W. Eikelboom, MBBS, and Theodore E. Warkentin, MD, both of McMaster University (Hamilton, Canada), caution that even though measuring immature platelets is easy and inexpensive, it is not ready for routine application to risk prediction or therapeutic choice. They note that several other biochemical markers are predictive of cardiovascular events, “but before being introduced into practice, we need evidence that measuring the marker will benefit patients.”

In a telephone interview with TCTMD, Deepak L. Bhatt, MD, MPH, of Brigham and Women’s Hospital (Boston, MA), said the current results are consistent with—but an incremental advance over—an earlier study correlating cardiovascular risk with mean platelet volume, which is a rough surrogate for immature platelet count.

Although the current study implies that high immature platelet levels contribute to future ischemic risk, the key question is whether they are simply a marker or a modifiable risk factor, he stressed, adding that immature platelets are like the residual reactivity detected by platelet function testing.

More Frequent Dosing a Possible Approach

Inflammation and even bleeding stimulate platelet turnover, Dr. Bhatt observed, and thus what looks like antiplatelet resistance might in fact stem from production of new platelets. “If you take aspirin or clopidogrel in the morning, they inactivate the platelets that are present at the time,” he explained. “But if the bone marrow is churning out immature platelets, they will not be inhibited.”

That is where twice-a-day dosing may be an advantage, he said, pointing to signals from other research that using such a strategy with aspirin may help suppress platelet reactivity in diabetics.

The finding that immature platelets are an independent risk factor needs to be confirmed in a larger study, Dr. Bhatt said, adding, “My guess is that it will be because it makes a lot of biological sense.” But the next, crucial step is to determine if it is a modifiable risk factor, he reiterated.

It would be interesting to see how measuring immature platelets stacks up against the current platelet function tests in terms of risk prognostication—whether it provides incremental information—and, further down the road, how it might fare in a panel of biomarkers for ischemic risk, he observed.

If measuring immature platelets does prove useful, “that would be great because it is easy to do and cheap,” Dr. Bhatt commented, adding that the test may well be adopted for other purposes, such as diagnosing the source of thrombocytopenia, so the information would be a welcome bonus.

Sources:
1. Ibrahim H, Schutt RC, Hannawi B, et al. Association of immature platelets with adverse cardiovascular outcomes. J Am Coll Cardiol. 2014;64:2122-2129.
2. Eikelboom JW, Warkentin TE. Immature platelet count: part of the cardiologist’s complete blood count [editorial]? J Am Coll Cardiol. 2014;64:2130-2132.

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