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Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) who develop postadmission thrombocytopenia are more likely to experience moderate-to-severe in-hospital bleeding, according to a post hoc study from the SYNERGY trial published online April 28, 2014, ahead of print in the American Heart Journal. Furthermore, severe thrombocytopenia is associated with increased 1-year mortality.

Investigators led by Amit N. Vora, MD, MPH, of the Duke Clinical Research Institute (Durham, NC), analyzed data from 7,435 NSTE-ACS patients with admission platelet counts of ≥ 150 x 10⁹/L enrolled in SYNERGY. The original study found no difference in 30-day rates of all-cause death or MI (primary efficacy endpoint) between patients randomized to enoxaparin or unfractionated heparin but did find an increase in TIMI major bleeding with enoxaparin.

The subanalysis looked at the 675 patients (9.1%) with mild in-hospital thrombocytopenia (nadir platelet count of 100-149 x 10⁹/L with < 50% drop from baseline) and 139 patients (1.9%) with severe thrombocytopenia (83 with a nadir platelet count of < 100 x 10⁹/L and 126 with a nadir representing a ≥ 50% drop from baseline).

Rates of antiplatelet and anticoagulation medication use as well as diagnostic catheterization were similar between patients who did and did not develop thrombocytopenia, although the former were more likely to undergo CABG. Upon discharge, patients with severe thrombocytopenia were less likely to be prescribed antiplatelet agents, though at 30 days there was no difference in use of evidence-based medications between patients with and without thrombocytopenia. Those with severe thrombocytopenia had persistently lower use of aspirin and clopidogrel compared with those with milder or no thrombocytopenia, although the difference did not reach statistical significance.

Bleeding Risk Rises with Severity of Thrombocytopenia

Rates of in-hospital GUSTO moderate-severe bleeding after the nadir platelet count were higher in patients who developed mild or severe thrombocytopenia compared with those who did not (table 1). After adjustment, mild thrombocytopenia remained associated with higher bleeding (adjusted HR 1.63; 95% CI 1.16-2.29), while severe thrombocytopenia increased bleeding almost sevenfold (adjusted HR 6.93; 95% CI 4.55-10.56). Each 10 x 10⁹/L reduction in platelet count below 170 x 10⁹/L was tied to incrementally higher GUSTO major bleeding risk (adjusted HR 1.22; 95% CI 1.17-1.27; P < .001). 

At 1 year, increasing severity of thrombocytopenia was also associated with higher rates of mortality from the time of platelet nadir (table 1). After multivariable adjustment, severe—but not mild—thrombocytopenia remained associated with an increase in mortality (adjusted HR 4.07; 95% CI 2.86-5.78). There was an incremental 18% risk of mortality for every 10 x 10⁹/L decrease in platelet count below 170 x 10⁹/L (adjusted HR 1.18; 95% CI 1.13-1.22; P < .001).

Table 1. In-Hospital Bleeding, 1-Year Mortality by Thrombocytopenia Severity

In a landmark analysis of patients who survived the index hospitalization, after adjustment for discharge medication use, there was no mortality difference between those with mild vs no thrombocytopenia. The relationship between severe thrombocytopenia and higher 1-year mortality persisted but was attenuated (adjusted HR 2.83; 95% CI 1.49-5.38).

“Given the complexity of pharmacotherapy assessed in recent ACS trials, including the combination of several potent antithrombotic and antiplatelet drugs with different mechanisms of action, the incidence of acquired thrombocytopenia has likely increased [over] the last years,” Eugenia Nikolsky, MD, PhD, of Rambam Medical Center (Haifa, Israel), told TCTMD in an email.

On the other hand, thrombocytopenia is significantly less common with use of bivalirudin compared with unfractionated heparin plus a glycoprotein IIb/IIIa inhibitor (GPI), she noted.

Beyond a certain threshold of thrombocytopenia, the first step should be to eliminate heparin if it has been administered, said Sunil V. Rao, MD, of Duke Clinical Research Institute (Durham, NC), in an email with TCTMD. Then, he and Dr. Nikolsky agreed, clinicians should try to understand the nature and source of the thrombocytopenia—eg, if it is characterized by decreased production or increased destruction of platelets and whether it may be due to an autoimmune mechanism.

Temper Reaction to Thrombocytopenia

Reducing antiplatelet therapy may be a “natural reaction to seeing thrombocytopenia,” Dr. Rao said, but these patients’ high bleeding risk must be balanced against the fact that they may be hypercoagulable in the face of thrombocytopenia, he cautioned.

Similarly, Dr. Nikolsky noted that although there is a strong relationship between lower platelet count and bleeding, “severe bleeding by itself may cause reduction in platelet count by the mechanism of disseminated intravascular coagulopathy.” Moreover, she pointed out, thrombocytopenia in the trial was related to older age, female gender, and worse renal function, which are all known bleeding predictors. “This supports in my mind that bleeding caused thrombocytopenia, and not vice versa,” she said.

In addition, Dr. Nikolsky observed, severe thrombocytopenia may be associated with several clinical scenarios including cardiogenic shock, multi-organ failure, and/or sepsis, and this might explain the high mortality seen in these patients.

Finally, Dr. Rao agreed with the authors that if ACS patients are discharged without antiplatelet therapy, they “should be monitored closely and frequently and have their antiplatelet therapy [re]started as soon as possible.”

Vora AN, Chenier M, Schulte PJ, et al. Long term outcomes associated with hospital acquired thrombocytopenia among patients with non-ST-segment elevation acute coronary syndrome. Am Heart J. 2014;Epub ahead of print.

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