In recent decades, Klebsiella pneumoniae (K. pneumoniae) has emerged as the primary pathogen for community-acquired liver abscesses in many Asian countries, surpassing Gram-positive cocci (Luo et al., 2016). Its hypermucoviscous phenotype is associated with a heightened risk of extrahepatic metastatic infections in K. pneumoniae liver abscess (KPLA), notably affecting the lungs, eyes, or brain (Fang et al., 2007; Tan et al., 2020). A significant occurrence of regional thrombophlebitis in hepatic veins has been observed in KPLA cases in contrast with other liver abscess etiologies (Alsaif et al., 2011).

Thrombocytopenia is characterized by platelet counts below 100×10^9/L and is prevalent among septic patients (Shannon, 2021). This condition has been linked to disease severity, including increased bleeding tendencies, higher transfusion requirements, and in-hospital death (Zhou et al., 2020). To date, there have been no studies investigating the relationship between thrombocytopenia and disease severity in KPLA. Beyond their primary role in hemostasis, platelets are integral to the immune system (Morrell et al., 2014). Their involvement in the immune response against infections, termed immunothrombosis, has garnered significant attention (Engelmann and Massberg, 2013). Platelets can adhere to bacteria, triggering a cascade of events that foster thrombus formation and ensuring its confinement to the injury site (Cox, 2023). In thrombophlebitis, platelets are activated and play an immunomodulatory role, leading to increased platelet consumption, which may be associated with thrombocytopenia in patients with KPLA. In addition, impaired bone marrow platelet production may be another potential cause of thrombocytopenia during infection.

Therefore, the objective of our study was to examine the relationship between thrombocytopenia and KPLA severity and to explore the underlying causes from the perspectives of platelet consumption and bone marrow platelet production.

Thrombocytopenia commonly coexists with various infectious diseases, such as sepsis (Thiery-Antier et al., 2016), community-acquired pneumonia (CAP) (Cunha and Hage, 2011), COVID-19(Zhao et al., 2020), and hepatitis B (Jiang et al., 2019), with an incidence ranging from 2% to 20.5%. It is often indicative of a more severe illness and a poorer clinical outcome, which is further supported by a recent study on PLA (Li et al., 2023). However, liver abscesses caused by K. pneumoniae commonly show distinct imaging features and clinical presentations compared to those caused by other bacteria, with higher rates of thrombophlebitis and extrahepatic metastatic infection (Chung et al., 2007; Alsaif et al., 2011). This is mainly attributed to its unique virulence factors, including up to four siderophore systems for iron acquisition, increased capsule production, K1 and K2 capsule types, and the colibactin toxin, along with antibiotic resistance (Fasciana et al., 2019; Choby et al., 2020). Therefore, our study is the first to specifically focus on the association between thrombocytopenia and KPLA severity and further analyzed the etiology of thrombocytopenia.

The present investigation corroborates the existing literature by revealing that KPLA patients with thrombocytopenia exhibit significantly enhanced inflammatory responses, heightened hepatic and renal dysfunction, and greater occurrence of adverse outcomes, including increased mortality. The etiology of this association may stem from the compromised immune system’s capabilities due to diminished platelet counts, which in turn exacerbates infection symptoms. In contrast, the progression of the infection itself may promote the degradation of platelets and hinder their synthesis (Klinger and Jelkmann, 2002; Zhou et al., 2020). Despite the intricacies of the relationship between thrombocytopenia and disease gravity, lower platelet counts portend a shift towards a more critical state, thereby demanding increased clinical vigilance. Interestingly, thrombocytosis has also been found to be a prognostic marker for negative outcomes in infectious diseases as detailed by Prina et al., who note its association with poor prognoses in CAP patients, including severe complications like pleural effusion and empyema (Prina et al., 2013). Further findings suggest a significant link between both thrombocytosis and thrombocytopenia and a higher risk of mortality in septic patients with leukocytosis (Bakey et al., 2013). This evidence highlights the influence of platelet count variations on the course and seriousness of sepsis, emphasizing the imperative for comprehensive research on the pathophysiological mechanisms involved.

The presence of a filling defect in the hepatic vein adjacent to a liver abscess is a distinctive and frequent radiographic manifestation of KPLA that is characterized as thrombophlebitis (Perez-Cruet et al., 1993; Hanazaki et al., 2001). Thrombophlebitis is theorized to arise from platelet activation subsequent to KP infection, triggering the coagulation cascade, which is a process known as immunothrombosis. It is feasible for immunothrombosis to occur at sites of infection, a phenomenon extensively documented in the pulmonary regions of COVID-19 patients (Kvietys et al., 2021). The hepatic vein near the abscess is particularly vulnerable to this condition, epitomizing a classic case of immunothrombosis. The present study’s multivariate analysis substantiated that thrombocytopenia is independently correlated with thrombophlebitis. This supports the conjecture that there is a significant activation and subsequent consumption of platelets during the process of immunothrombosis associated with KPLA (Engelmann and Massberg, 2013; Cox, 2023).

Our prior research has established poor glycemic control as a pivotal factor in KPLA propagation to extrahepatic metastatic infection (Wang et al., 2022). The present study further revealed that poor glycemic control is intricately linked to thrombophlebitis in an independent manner. It has been documented by Lee et al. that diabetic individuals with HbA1c levels of ≥9% are predisposed to enhanced platelet activation, consequently exhibiting elevated occurrences of hepatic venous thrombophlebitis (Lee et al., 2018). The precise mechanisms by which diabetes escalates the risk of thrombophlebitis remain to be fully understood. However, this phenomenon can be attributable to heightened platelet reactivity or irregular activation within the coagulation pathway. Moreover, the escalation in platelet activation and subsequent immunothrombosis may induce increased peripheral platelet consumption, which can then accelerate the onset of thrombocytopenia.

In the present investigation, comprehensive data on patients with KPLA were collected from various departments. Notably, a subset of these patients was subjected to bone marrow aspiration tests within the infectious diseases department, thus enabling the examination of the potential link between thrombocytopenia and suppressed bone marrow platelet synthesis. The study findings point towards compromised bone marrow platelet production as the primary contributor to thrombocytopenia, which is presumably connected to the septic condition incited by KPLA. Sepsis-induced inflammatory cytokines can compromise bone marrow stem cells, reducing megakaryocyte levels and impairing platelet production (Frydman et al., 2023). Additionally, hemophagocytosis, which is a condition marked by macrophages consuming blood cells, was observed in half of the thrombocytopenic KPLA patients (Zoller et al., 2011). This phenomenon can occur in severe inflammatory conditions, including sepsis (Ito et al., 2006; Castillo and Carcillo, 2009), influenza (Ando et al., 2006), and malaria (Zoller et al., 2011; Klein and Ronez, 2012), potentially exacerbating bone marrow platelet production deficits (François et al., 1997; Stéphan et al., 1999; Buyse et al., 2010). Furthermore, KPLA-related liver damage may cause TPO deficiency, which is crucial for platelet production and is primarily liver-derived, leading to decreased platelet counts (Lee-Sundlov et al., 2022). Infections can also trigger sialidase release, hydrolyzing sialic acid on platelets and thus inducing thrombocytopenia (Li et al., 2017).

Contemporary research suggests that the utility of transfusion or pharmacotherapy for infection-related thrombocytopenia may be circumscribed. The cornerstone of thrombocytopenia management is the resolution of the underlying infection, which is exemplified by prompt drainage in cases such as PLA, where puncture does not exacerbate bleeding risks even in the presence of coagulopathy (Wang et al., 2021). Adequate drainage and appropriate long-term antibiotic therapy, particularly with carbapenems such as meropenem, imipenem, and ertapenem, are beneficial for treating KPLA and can reduce associated mortality risk (Di Carlo et al., 2011; Chong et al., 2018; Di Carlo et al., 2019). However, for carbapenem-resistant Klebsiella pneumoniae, treatment options are limited, resulting in high mortality rates among ICU patients (Mammina et al., 2012; Boyd et al., 2017). Platelet count resurgence typically trails behind clinical improvement (Menard et al., 2019). A protracted absence of platelet recovery is often indicative of a more severe disease and correlates with adverse clinical prognoses. Additionally, the timelines for platelet count normalization observed in our study parallel those documented in sepsis and septic shock cases (Li et al., 2017; Menard et al., 2019).

Our study had some limitations. First, the inability to directly measure markers of platelet destruction and depletion led us to infer platelet consumption from the characteristic presentation of thrombophlebitis. Second, the heterogeneity in patient management across different hospital departments resulted in inconsistent treatment regimens, which could have influenced the outcomes. Third, detailed differential analysis of bone marrow findings was lacking, which was primarily due to the small number of KPLA patients at Shengjing hospital who underwent bone marrow aspiration. To overcome these limitations and corroborate the study findings, further research involving larger-scale, multi-center studies is recommended.

In conclusion, the identification of thrombocytopenia serves as a crucial marker for determining KPLA severity. Diminished platelet production within the bone marrow coupled with escalated consumption of platelets in the periphery likely constitute the primary pathophysiological underpinnings of thrombocytopenia in patients with KPLA.

The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.

The studies involving humans were approved by the Ethics Committee of the Shengjing Hospital of China Medical University. The studies were conducted in accordance with the local legislation and institutional requirements. The ethics committee/institutional review board waived the requirement of written informed consent for participation from the participants or the participants’ legal guardians/next of kin because Patients’ identification remained anonymous and informed consent was waived due to the observational nature of the study.

LC: Writing – original draft, Methodology, Investigation, Formal Analysis, Data curation, Conceptualization. HW: Investigation, Writing – original draft, Methodology, Formal Analysis, Data curation, Conceptualization. HW: Writing – original draft, Formal Analysis, Data curation. YG: Writing – original draft, Validation, Methodology. ZC: Writing – review & editing, Supervision, Resources, Methodology, Investigation, Funding acquisition, Formal Analysis, Data curation, Conceptualization.