BCIs have been recognized for their diagnostic, pathophysiological, and prognostic value in sepsis, but their causal role, and if so, their causal direction, remain uncertain. This study aimed to explore the causal relationships between BCIs and 28-day mortality in sepsis by conducting an MR analysis. While strikingly, we found a remarkable and consistent genetic association between PDW and 28-day mortality in sepsis risk in both UVMR and MVMR models. However, no significant associations of genetic liability to other BCIs were observed, which is inconsistent with previous findings 11–15.
Traditionally, platelets are typically known for their role in hemostasis; however, recent evidence highlights their significant involvement in sepsis, inflammation, and immune responses6,20. Various cohort studies have emphasized the importance of platelet parameters such as PLC, PDW, and MPV in the early diagnosis and prognosis of sepsis12,13,36–38, although some studies question their prognostic value16,39. In line with prior research, our MR study provided evidence that a genetic predisposition to higher PDW is independently and causally associated with an increased risk of 28-day mortality in sepsis (IVW: OR, 1.12; 95% CI, 1.06–1.26; P < 0.05). However, unlike previous studies, we found no obvious evidence that genetic predisposition to PLC and MPV are causally associated with the risk of mortality in sepsis.
Nevertheless, a larger question is how PDW affects the prognosis of sepsis, and why MPV, another indicator of platelet size, has no relationship with sepsis mortality. PDW serves as an indicator of the morphological variability within platelets and is potentially linked to their functional status and production rate40. Therefore, an elevated PDW may reflect the activated state of platelets. In the context of sepsis, platelets experience heightened activation and aggregation, subsequently culminating in the formation of microvascular thrombosis41. Consequently, heightened PDW levels may signify an augmented risk of platelet aggregation and thrombus development, thereby contributing to compromised microcirculation, organ hypoperfusion, and multi-organ dysfunction41,42. In contrast, MPV only reflects the average volume and may not capture the variability in their functional activity.
On the other hand, increased PDW may also be related to the inflammatory state of sepsis patients. Activated platelets are capable of releasing a large number of inflammatory mediators, thereby modulating the response of leukocytes and endothelial cells to inflammatory stimuli43. When platelets are activated, they can secrete a plethora of chemotactic factors, cytokines, and adhesion molecules, such as IL-1, CXCL1, and PF4 44. Among them, IL-1 acts as a central mediator in the cascade of cytokine reactions, further inducing vascular smooth muscle cells to release IL-6 and IL-8, as well as endothelial cells to release CCL245,46. The ensuing inflammatory reactions can precipitate a cascade of events including a cytokine storm, endothelial cell injury, release of tissue factors, and activation of the coagulation cascade, ultimately leading to the development of disseminated intravascular coagulation (DIC), propensity for bleeding, and shock6,42. Moreover, platelets can also form aggregates with leukocytes, exerting further influence on leukocyte functionality43. Platelet-leukocyte interactions can further enhance the adhesion characteristics and phagocytic activity of neutrophils, inducing an inflammatory response, which is crucial in the innate immune system for combating microbial infections47. However, in sepsis, there is excessive activation of the innate immune system, particularly neutrophil hyperactivation, which is associated with tissue damage, multi-organ failure, DIC, and other microvascular pathologies48. Furthermore, abundant evidence has shown that pathogens such as Staphylococcus aureus, Streptococcus pneumoniae, and Escherichia coli can bind to platelets and further activate platelet function49, which may play a crucial role in the pathogenesis of sepsis.
As for the leukocyte and erythrocyte indices, although previous studies have indicated that most of them, such as RDW, are associated with the prognosis of sepsis17, our MR analysis did not find any significant causal correlation. Furthermore, our study also provided new insights into some controversial issues. For example, RDW has been considered a valid prognostic marker in most studies, but some studies have challenged its importance16,17,39. Our study found that RDW had no clear causal association with sepsis severity (Fig. 3). In summary, to elucidate the intricate interplay between these hematological indices and sepsis, future research endeavors should focus on unraveling the underlying molecular pathways and biological mechanisms involved.
Strengths and limitations
We used summary genetic associations from the largest GWASs available, which are crucial for identifying small effect sizes. Moreover, the utilization of the MVMR model represents a significant strength. MVMR enables the incorporation of multiple genetic variants, accounting for their effects on both the exposure and outcome variables. To our knowledge, this is the first study using two-sample MR analysis to investigate the causal relationship between BCIs and mortality risk in sepsis.
However, the results should be interpreted cautiously due to the following limitations. Despite the large sample size used in our analysis, we acknowledge the possibility of overlooking weak associations, especially those involving exposures composed of some SNPs that can explain small phenotypic variations. In addition, it is important to recognize the potential for bias resulting from horizontal pleiotropy. we found consistent results across various sensitivity analyses, and limited evidence of significant pleiotropic effects was observed in MR-Egger and MR-PRESSO analyses. Thirdly, the lack of detailed clinical data prevented us from performing subgroup analyses, which could introduce potential biases. Fourth, the population restriction in our study may constrain the applicability of our findings to other populations.