Myelodysplastic syndromes (MDS) are one of the most prevalent hematological malignancies originating from hematopoietic stem/progenitor cells. It is a very heterogeneous group of myeloid disorders characterized by somatic mutations in hematopoietic stem cells, leading to ineffective hematopoiesis, bone marrow dysplasia, and an increased risk of transformation to acute leukemia (1).

The prevalence of MDS increases with age. The choice and timing of therapy depend on the risk stratification. The International Prognostic Scoring System (IPSS) (2) and revised International Prognostic Scoring System (IPSS-R) (3) are the most commonly used prognostic models. In general, all these scoring systems include the analyses of peripheral cytopenias, percentage of blasts in the bone marrow, and cytogenetic characteristics. Patients with MDS are generally divided into two different broad subgroups according to two scoring systems: lower- and higher-risk groups. Patients with a lower risk group by IPSS are those with low and intermediate-1(INT-1) diseases and very low, low, and some subsets of intermediate risk by the IPSS-R. Patients with a higher-risk disease are those with intermediate-2 (INT-2) and high risk by the IPSS and some subsets of intermediate-, high-, and very high-risk disease by the IPSS-R. Although the IPSS and IPSS-R are very important and serve as part of the main eligibility criteria for past and ongoing registration in clinical trials, many limitations remain.

With the deepening of biomarker research, various types of indicators, including genetics, blood parameters, and even nutritional indexes, had been found to be related to the biological characteristics and even the prognosis of MDS (4–6). Therefore, the concise indexes may help to more accurately evaluate the prognosis of MDS.

The platelet large–cell ratio (P-LCR) is an index representing the percentage of platelets larger than 12 fl in the circulating pool (7), generated by the automatic blood cell counter, thus probably identifying those platelets that are metabolically and enzymatically more active than small platelets, and it is easily available at an affordable cost. The original description of this parameter is from 1981 (7). It is determined based on flow cytometry and automated blood cell analysis techniques. The P-LCR was the best tool to assess megakaryocyte activity and a good monitoring tool for platelet activity. Evidence has indicated that the P-LCR contributes to the diagnosis of certain diseases (8–10). For instance, the P-LCR was proven higher in patients with chronic myeloid leukemia than patients with reactive thrombocytosis, essential thrombocythemia, or polycythemia vera (11). In clinical practice, abnormal platelet parameters are relatively common in MDS patients at initial diagnosis, but its impact on the prognosis remains unclear.

In this study, we performed a retrospective review to evaluate whether the P-LCR is associated with the prognosis of MDS.

The present study showed that the P-LCR level at diagnosis was associated with the prognosis in patients with MDS. As far as we are aware, this study is the first report showing the P-LCR as an independent prognostic variable in MDS. We found that the patients whose P-LCR level was less than 36.7% at diagnosis experienced shorter overall survival compared to patients with a high P-LCR. There seems to be a similar tendency in the relationship between the P-LCR and PFS. PFS in the P-LCR^low group seemed to be shorter compared to the P-LCR^high group, although it was not statistically significant in the presented data. Subgroup analyses indicated that the P-LCR has a higher prognostic value in patients with higher risk.

Univariate and multivariate analyses were also performed to investigate the prognostic factors affecting disease progression and death. Results indicated that the P-LCR is a prognostic parameter in patients with MDS. Although the mechanism of action is still unclear, there is a consensus that the P-LCR is a potential biomarker, which can be quickly and accurately detected in peripheral blood test. Moreover, the baseline platelet count seemingly has a prognostic impact in MDS. While various studies have evaluated the prognostic significance of thrombocytosis in cancers, such as colon cancer, ovarian cancer, and hepatocellular cancer (13–15), no significance for platelet count in MDS has been reported. Gender seems to influence the prognosis of MDS patients; the same conclusion was also found in previous studies (16, 17). Some possible explanations for that might include 1) the increased comorbidities upon diagnosis in male patients, which limited preferred choices and the aggressiveness of treatment options (18, 19), while large cohort-based studies confirmed that MDS patients with the above comorbidities had significantly greater risk of death than those without comorbidities (20); 2) male MDS patients might be associated with molecular abnormalities such as faster methylome aging and shorter telomeres (21), both of which often correlate with shorter survival (22).

The present data suggested that the elevated P-LCR level at diagnosis was associated with better prognosis in MDS patients, especially for those with higher risk disease. We speculate that the reasons may be that, firstly, more large platelets are involved in the neoplastic consumed, thereby speeding up the progression of the tumor (23); secondly, the degree of platelet activation affects various effector factors, such as Vascular Endothelial Growth Factor (VEGF), Epidermal Growth Factor (EGF), transforming growth factor-beta (TGFβ), Platelet-derived growth factor (PDGF), and Interleukin-6 (IL-6), that impact vascular maturation in the tumor microenvironment and mediate the invasion of cancer cells (24), which are associated with survival in MDS. Third, large platelet cells might be associated with greater platelet–tumor complex formation; therefore, patients with a high P-LCR could gain more benefit from antiplatelet drugs than could patients with low P-LCR levels (25).

Platelets play a critical role in the development and progression of different cancers by promoting cancer cell proliferation, survival, angiogenesis, and metastasis (26, 27). There have been several studies revealing that platelet indices are associated with prognosis in patients with various diseases. Thrombocytosis was related to poor prognosis in several cancers, such as ovarian, gastric, lung, breast, hepatocellular, and bladder cancer (28–33). Higher platelet distribution width (PDW) was correlated with unfavorable prognosis in ovarian, and breast cancer (34, 35). Moreover, the mean platelet volume (MPV) level was evaluated for association with the development of diabetes mellitus (36) and outcomes of cancer patients (37, 38). However, the impact of the P-LCR in MDS is unclear.

The platelet–large cell ratio (P-LCR) is an indicator of circulating larger platelets (>12 fl) and the best tool to assess megakaryocyte activity (24). A large platelet is somehow a representative marker of immature platelets; thus, the lower P-LCR observed in MDS patients in comparison to the respectively high group suggests increased platelet maturity. These findings are also similar to those of Renate Asare et al. (39), whose results suggested that there are significantly (p<0.05) lower levels of P-LCR in children with Burkitt lymphoma than the controls. The mechanisms for the phenomenon remain uncertain. Psaila et al. (40) found that patients with AML/MDS had smaller platelets and lower in vivo platelet activation and ex vivo platelet reactivity than patients with immune thrombocytopenia. All these studies prompt that the flow cytometric analyses of platelet function and cell parameter analyzers could establish the expression of the platelet indices and reflect the megakaryocyte activity, so as to judge the marrow environment indirectly. The P-LCR has good prognostic evaluation efficiency and could also reflect the changes of the general states of MDS from different aspects. As an easily obtained index, it may help to more accurately evaluate the prognosis of MDS.

This is the first documentation on the prognostic value of P-LCR in patients with MDS with long-term follow-up. However, our data are preliminary; further prospective analyses and the mechanism studies are necessary.

The original contributions presented in the study are included in the article/ Supplementary Material . Further inquiries can be directed to the corresponding authors.

The studies involving human participants were reviewed and approved by Institutional Review Committee of Huai’an No.1 People’s Hospital. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.

LY designed the study. QC and YC wrote the manuscript. YZ collected data. LZ and KC were responsible for the tables. ZH was responsible for the figures. CW and LY modified the manuscript.

This work was funded by Science and Technology Fund of Huaian City [grant # HAB202020] and Commission of Health of Jiangsu Province [grant # 2019082].

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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