Editorial: importance of an elevated mean platelet volume for prediction of major adverse cardiovascular events in non-alcoholic fatty liver disease

Larger mean platelet volume (MPV), which typically reflects platelet hyper-reactivity, is a useful prognostic marker in patients with cardiovascular disease (1). A recent meta-analysis of eight cross-sectional studies showed that patients with NAFLD had higher MPV values (2). Although cardiovascular disease is the leading cause of death in NAFLD (3), further research is needed to establish whether larger MPV predicts major adverse cardiovascular events (MACE) in patients with NAFLD. On this background of evidence, the findings of Abeles et al. (4) add a further critical piece of information, showing that NAFLD patients with larger MPV are more likely to develop incident MACE. Indeed, in retrospective (365 middle-aged patients with imaging-defined or biopsy-proven NAFLD) and prospective (111 patients) validation NAFLD cohort study, MPV was found to be independently associated with 1-year risk of MACE (adjusted-hazard ratio 2.9; 95%CI 1.9-3.7), along with older age and diabetes (4). By calculating a bespoke risk score, termed the NAFLD CV-risk score (including the weighted sum of age, MPV and pre-existing diabetes), the area under ROC curve for predicting MACE in the derivation cohort was 0.84 for NAFLD CV-risk score and 0.83 for MPV alone, respectively. A cut-off of NAFLD CV-risk score of −3.98 yielded 97% sensitivity, 27% specificity, 16% positive predictive value (PPV) and 99% negative predictive value (NPV). A cut-off of MPV >10.05 fL yielded 97% sensitivity, 59% specificity, 24% PPV and 97% NPV. Notably, the authors also found that the NAFLD CV-risk score had satisfactory performance for predicting MACE in the validation cohort and, more importantly, outperformed the Framingham and QRISK2 risk equations in the whole study cohort (4). However, it is important to underline that the two aforementioned established risk equations have been developed for identifying 10% risk of MACE at 10 years rather than 1-year risk. Additionally, the NAFLD CV-risk score had a high NPV, but a very low PPV (4). On this line of reasoning, there are still many unresolved biological and analytical drawbacks challenging the real clinical usefulness of MPV (Table 1). First, it remains uncertain whether larger platelets are a cause or consequence of thrombosis, or both. Then, many genetic and acquired factors influence platelet volume (e.g., age, sex, smoking, hypertension, diabetes and some genetic polymorphisms) (5). The biological variation of MPV is another drawback. The inter-individual biological variability of MPV is ~7% in healthy individuals, so that differences lower than this threshold shall not be considered clinically significant (6). Multiple analytical issues also plague the MPV assessment (e.g., different analytical techniques, high inter-instrument variability, relatively poor analytical performance and analytical interference from cellular fragments and other debris present in the blood)(7-9). Collectively, the findings of the study by Abeles et al. (4) confirm that NAFLD patients should undergo careful cardiovascular surveillance, as recommended by the most recent US clinical practice guidelines (10). However, large prospective studies with longer follow-ups are needed to confirm the validity of this new NAFLD CV-risk score for predicting MACE and unravel the complex pathophysiological role of platelets in patients with NAFLD.