Reply: “Letter to the editor: Are we comparing apples with oranges?”
Authors: Benedikt Silvester Hofer, Thomas Reiberger, Thomas Gremmel
Journal: Hepatology (2024)

We would like to thank Drs Zanetto, Campello, Senzolo, and Simioni1 for their interest in our work on the prognostic implications of altered platelet activation in cirrhosis.2 We greatly appreciate their effort to reanalyze their data on the prognostic role of platelet aggregation (measured by Multiplate and divided by platelet count, ie, "PLT"),3 now accounting for C-reactive protein. Importantly, C-reactive protein, in addition to the PLT remained independently associated with the composite end point of further decompensation, progression to transplantation, and liver-related death, highlighting the relevance of systemic inflammation. The authors refer to differences between the studied populations, that is, stable outpatients in our study2 versus unstable hospitalized patients included by Zanetto et al3. We thus conducted a subgroup analysis of 40 patients with decompensated cirrhosis and hepatic impairment (Child-Pugh B/C) undergoing same-day HVPG and platelet activation measurements. Median Model for End-Stage Liver Disease (MELD) was 15 (14–18), HVPG was 21 (20–23) mm Hg, C-reactive protein was 0.58 (0.25–1.20) mg/dL, and median IL-6 was 14.3 (8.8–30.3) pg/mL. Over a median follow-up of 24.4 (16.3–34.4) months, 17 patients (43%) experienced further decompensation and 11 died (28%). When analyzing prognostic implications, we observed that, similar to the findings in our overall study population, higher platelet surface P-selectin expression was associated with better outcomes. Specifically, more pronounced protease-activated receptor-4-mediated platelet activation was significantly linked to a lower risk of further decompensation (HR per 100 median fluorescence intensity:0.84 [95% CI:0.73–0.97]; p=0.020), even after accounting for MELD and HVPG (adjusted HR [aHR]:0.82; p = 0.011) or MELD and IL-6 (aHR:0.83; p = 0.013). Furthermore, higher protease-activated receptor-1-mediated platelet activation was associated with significantly longer transplant-free survival (HR per 100 median fluorescence intensity:0.89 [95% CI:0.80–0.98]; p = 0.014), even after adjusting for either MELD (aHR:0.89; p = 0.019), HVPG (aHR:0.89; p = 0.014) or IL-6 (aHR:0.90; p = 0.049). These findings underline that, even in a population more comparable to the one studied by Zanetto et al1,3, preserved platelet responsiveness to thrombin-receptor agonists indicates a lower risk for liver-related events. In vivo platelet function and primary hemostasis in cirrhosis are influenced by a variety of factors. Thus, when using in vitro tests to study hemostasis in cirrhosis, it is of utmost importance to first elucidate the independent contribution of all involved factors. Techniques not affected by platelet count or volume, such as flow cytometry, seem to convey certain advantages and allow for the evaluation of platelet responses to different agonists. In conclusion, we appreciate the efforts and comments by Drs Zanetto et al1, which underline that platelet (dys-)function indeed has an important role in cirrhosis and is increasingly recognized as a valuable prognostic marker for decompensation and mortality.