Staphylococcus aureus increases platelet reactivity in patients with infective endocarditis

Abstract

Thromboembolism is frequent in infective endocarditis (IE). However, the optimal antithrombotic regimen in IE is unknown. Staphylococcus aureus (SA) is the leading cause of IE. First studies emphasize increased platelet reactivity by SA. In this pilot study, we hypothesized that platelet reactivity is increased in patients with SA- IE, which could be abrogated by antiplatelet medication. We conducted a prospective, observatory, single-center cohort study in 114 patients with IE, with four cohorts: (1) SA coagulase positive IE without aspirin (ASA) medication, (2) coagulase negative IE without ASA, (3) SA coagulase positive IE with ASA, (4) coagulase negative IE with ASA. Platelet function was measured by Multiplate electrode aggregometry, blood clotting by ROTEM thromboelastometry. Bleeding events were assessed according to TIMI classification. In ASA-naïve patients, aggregation with ADP was increased with coag. pos. IE (coagulase negative: 39.47 ± 4.13 AUC vs. coagulase positive: 59.46 ± 8.19 AUC, p = 0.0219). This was abrogated with ASA medication (coagulase negative: 42.4 ± 4.67 AUC vs. coagulase positive: 45.11 ± 6.063 AUC p = 0.7824). Aspirin did not increase bleeding in SA positive patients. However, in SA negative patients with aspirin, red blood cell transfusions were enhanced. SA coagulase positive IE is associated with increased platelet reactivity. This could be abrogated by aspirin without increased bleeding risk. The results of this pilot study suggest that ASA might be beneficial in SA coagulase positive IE. This needs to be confirmed in clinical trials.

Figure 1

Study design as flowchart.

Figure 2

Platelet aggregation measured by Multiplate^® in patients with coagulase negative (n = 38/n = 53) and SA coagulase positive (n = 14/n = 9) infective endocarditis without and with antiplatelet medication. (A) ADP induced platelet aggregation, measured by MEA as area under the curve (AUC), was significantly higher in patients with SA+ IE in patients without antiplatelet medication while aggregation with TRAP did not differ between groups compared using two tailed t tests (SA−/ASA−: 39.47 ± 4.13 AUC vs. SA+/ASA−: 59.46 ± 8.19 AUC, p = 0.0219; TRAP—SA−/ASA−: 85.08 ± 5.075 AUC vs. SA+/ASA−: 91.46 ± 9.715 AUC, p = 0.5368). (B) ADP and TRAP induced platelet aggregation showed no differences depending on coagulase status in patients with IE and antiplatelet medication (ADP—SA−/ASA+: 42.4 ± 4.67 AUC vs. SA+/ASA+: 45.11 ± 6.063 AUC p = 0.7824; TRAP—SA−/ASA+: 84.78 ± 5.407 AUC vs. SA+/ASA+: 77.11 ± 7.725 AUC p = 0.5608).

Figure 3

Blood clotting measured by ROTEM^® and coagulation parameters in patients with coagulase negative (n = 38/n = 53) and SA coagulase positive (n = 14/n = 9) infective endocarditis without and with antiplatelet medication. (A) Blood clotting parameters FIBTEM A10, EXTEM CT and INTEM CT measured by ROTEM^® showed no differences between groups (FIBTEM A10—SA−/ASA−: 27.94 ± 1.63 mm vs. SA+/ASA−: 32.85 ± 2.648 mm AUC vs. SA−/ASA+: 28.29 ± 1.45 mm vs. SA+/ASA+: 28.78 ± 3.25 mm AUC, p = 0.4637; EXTEM CT—SA−/ASA−:55.56 ± 1.945 s vs. SA+/ASA−: 61.62 ± 5.144 s vs. SA−/ASA+: 55.96 ± 1.471 s vs. SA+/ASA+: 57.78 ± 4.904 s, p = 0.4590; INTEM CT—SA−/ASA−: 141.6 ± 6.022 s vs. SA+/ASA−: 160.2 ± 7.597 s vs. SA−/ASA+: 147.8 ± 3.258 s vs. SA+/ASA+: 154.9 ± 2.318 s, p = 0.1833). (B) Basic coagulation parameters Quick, INR, PTT did not differ between groups (Quick—SA−/ASA−: 74.03 ± 3.021% vs. SA+/ASA−: 71.77 ± 4.684% vs. SA−/ASA+: 74.27 ± 2.687% vs. SA+/ASA+: 66.44 ± 6.539%, p = 0.6777; INR—SA−/ASA−: 1.414 ± 0.2344 vs. SA+/ASA−: 1.16 ± 0.04 vs. SA−/ASA+: 1.167 ± 0.035 vs. SA+/ASA+: 1.25 ± 0.15, p = 0.4624; PTT—SA−/ASA−: 26.83 ± 0.7802 s vs. SA+/ASA−: 29.77 ± 2.964 s vs. SA−/ASA+: 27.51 ± 0.756 s vs. SA+/ASA+: 28.56 ± 2.31 s, p = 0.4934). One-way ANOVA was used for all comparisons.

Figure 4

Amount of perioperative erythrocyte transfusion in patients with coagulase negative (n = 38/n = 53) and SA coagulase positive (n = 14/n = 9) infective endocarditis without and with antiplatelet medication. The amount of erythrocyte transfusion was more frequent in SA− patients with acetylsalicylic acid (ASA) medication. Red blood cell transfusions did not differ between patients without ASA and patients with SA+ endocarditis with ASA (Erythrocyte transfusions—SA−/ASA−: 5.364 ± 5.719 transfusions; SA+/ASA−: 5.231 ± 4.285 transfusions; SA−/ASA+: 8.686 ± 9.195 transfusions; SA+/ASA+: 5.143 ± 3.078 transfusions). Non-parametric Kruskal–Wallis test was used adjusted for multiple group comparison by two-stage linear step-up procedure of Benjamini, Krieger and Yekutieli.