The Prognostic Impact of the Platelet Dynamics and Subthreshold Thrombocytopenia in Intensive Care Patients: A Prospective Cohort Study

The Prognostic Impact of the Platelet Dynamics and Subthreshold Thrombocytopenia in Intensive Care Patients: A Prospective Cohort Study | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article The Prognostic Impact of the Platelet Dynamics and Subthreshold Thrombocytopenia in Intensive Care Patients: A Prospective Cohort Study Kamil Deveci, Maruf Boran, Kübra E. Bahar, Fatma Sarıdağ This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9178594/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted 11 You are reading this latest preprint version Abstract Background Thrombocytopenia (TP) is common in intensive care unit (ICU) patients and has been associated with increased morbidity and mortality. However, the prognostic importance of platelet dynamics remains incompletely understood. We aimed to evaluate the prognostic impact of platelet dynamics and subthreshold/relative thrombocytopenia (< 200 ×10⁹/L) in ICU patients. Methods In this prospective observational cohort study, 280 adult patients admitted to the medical ICU were followed. TP was defined as PC < 150 ×10 9 /L and Subthreshold thrombocytopenia (STP) as PC < 200 ×10 9 /L. Patients were evaluated according to the presence, severity, duration (≥ 3 days vs < 3 days), and timing of TP (initial vs ICU-acquired). Clinical outcomes were analyzed. Multivariable logistic regression models was performed to determine independent predictors of ICU mortality. Results TP occurred in 42.1% of patients and was strongly associated with increased ICU, hospital, 28-day, and 90-day mortality (all p < 0.001). Mortality increased progressively with greater TP severity. Persistent TP (≥ 3 days) was independently associated with ICU mortality (aOR 2.75, 95% CI 1.50–5.02). Platelet count alone demonstrated limited discriminatory ability for predicting ICU mortality (AUC 0.58). Notably, a platelet threshold around 200 ×10⁹/L provided a more balanced sensitivity and specificity compared with the conventional 150 ×10⁹/L cut-off. Patients with STP showed greater disease severity and increased ICU mortality and need for organ support. Conclusions Beyond its presence alone, the severity and persistence of TP provide important prognostic information in critically ill patients. Our findings suggest that STP may represent an early marker of clinical deterioration, highlighting the potential role of STP as a dynamic biomarker for early risk stratification in ICU populations Health sciences/Biomarkers Health sciences/Diseases Health sciences/Medical research Health sciences/Risk factors Persistent Thrombocytopenia Relative Thrombocytopenia Platelet Dynamics Subthreshold Thrombocytopenia Mortality Figures Figure 1 Figure 2 Background Platelets are short-lived, nucleated blood components that play an important role in haemostasis as well as in immune regulation, inflammation and endothelial interaction 1 . A decrease in platelet count (PC) is defined as thrombocytopenia (TP), and although previous publications have used different threshold values (≤ 200 ×10 9 /L, ≤ 80 ×10 9 /L, ≤ 60 ×10 9 /L) and rates of decrease (< 30%, 50%) 2 , current literature defines TP as a PC below 150 ×10 9 /L 3 . It is quite common in intensive care units (ICUs); reported prevalence rates vary considerably across studies (8–56%) 2–4 . Many causes of TP, such as sepsis, medications, trauma, and haemodilution, may coexist in critically ill patients 5 , 6 . Among these aetiologies, sepsis remains the most important cause of TP in the ICU and has led to the widespread use of the term “sepsis-associated thrombocytopenia” in the literature 7 , 8 . TP increases the risk of bleeding, length of stay (LOS) in the ICU/hospital, and the need for life support devices, vasopressors, and mortality 5 , 9 , 10 . A linear relationship has been found between the severity of TP and mortality and disease severity 11 , 12 . Moreover TP lasting longer than three days has been associated with poor prognosis and mortality 8 . Particularly in severe TP, fear of bleeding leads to delay in invasive procedures, postponement of prophylactic anticoagulation, and platelet transfusions 5 , 13 , 14 . Correcting one factor in the treatment of TP patients may not always lead to clinical improvement 11 . The most important aspect of treatment is to correct the underlying disease, if possible. TP may be present at admission to the ICU or may develop during the course of treatment. The development of TP should be considered a consequence of the severity of the disease and the critical condition 15 . Therefore, monitoring the course of PC and the duration of TP is important in clinical follow-up. Our primary objective was to evaluate the prognostic impact of platelet dynamics, including the presence, timing, and duration of TP in the ICU, on mortality and clinical outcomes, and to investigate whether there is a relationship between platelet counts below 200 x 10⁹/L (subthreshold thrombocytopenia) and clinical outcomes. Patients and methods Study Population : This observational prospective cohort study was conducted in accordance with the STROBE Statement 16 for cohort studies. The study was conducted at Medical Intensive Care Unit-3 of Kayseri City Education and Research Hospital in Kayseri, Turkey. All consecutive patients aged 18 years and older admitted to the ICU and followed for more than 24 hours were eligible for inclusion in the study and had no missing critical information (death, organ failure, need for life support devices, need for blood product replacement) in their records. Patients with known terminal-stage solid or haematological malignancies, patients undergoing active chemotherapy, patients with end-stage (Child-pugh class C) liver cirrhosis, and patients with uncontrolled bleeding during hospitalisation were excluded from the study at the outset because they were associated with platelet abnormalities, regardless of their critical illness status. Inclusion of such patients could confound platelet kinetics and outcome analyses (Fig. 1 ). Of the 415 patients evaluated, 280 met the predefined inclusion criteria and were enrolled. Patients were followed until they were discharged from the hospital or for 90 days. The study was approved by the Institutional Ethics Committee (protocol number 2023–877). Patient enrollment began in September 2023 and ended in August 2024. All methods were performed in accordance with the relevant guidelines and regulations, in line with the principles of the Declaration of Helsinki. All patients provided written informed consent. Due to its single-centre design and predefined exclusion criteria, selection bias cannot be entirely eliminated, and the findings may not be generalisable to all ICU populations, particularly surgical or haematology-focused cohorts. Study Procedure : Patient eligibility was assessed upon admission to the ICU. Patients who met the inclusion criteria were informed about the study and enrolled on the same day. In line with the study objectives, standard ICU management protocols were applied without modification. Sample Size A pre-trial sample size calculation was performed using G*Power (version 3.1). Assuming a two-tailed alpha value of 0.05, statistical power of 80%, and a 20% difference in mortality rates between patients with and without thrombocytopenia (40% vs. 20%), a minimum of 104 patients were required. The final cohort comprised 280 patients, significantly exceeding the estimated requirement and thus enhancing the statistical precision of the analyses. Study Data Clinical data were obtained from patient medical records and the hospital's electronic medical record system (KEYDATA). The variables collected included demographic characteristics, comorbidities, reason for admission to the ICU, disease severity scores, therapeutic interventions, transfusion requirements, laboratory parameters, and clinical outcomes. The APACHE-II Score was calculated based on the worst values recorded within the first 24 hours of admission to the ICU. The SOFA score was calculated based on the values at the time of admission to the ICU. Recorded therapeutic interventions included anticoagulant and corticosteroid use, vasopressor support (VS), central venous catheter (CVC) placement, mechanical ventilation (MV), renal replacement therapy (RRT), and transfusion data. Laboratory variables included complete blood count (CBC) parameters, biochemical markers, inflammatory markers, coagulation parameters, and arterial blood gas measurements. Platelet counts (PC) were measured using impedance-based analysers and verified by optical methods when necessary. Peripheral blood smears were examined when clinically indicated. Routine laboratory assessments were performed at least once daily as part of standard ICU monitoring. Definitions Thrombocytopenia (TP) is defined as a PC < 150 ×10 9 /L. Relative Thrombocytopenia (RTP) or subthreshold thrombocytopenia (STP) is defined as PC < 200 ×10 9 /L. The RTP threshold was selected based on previous literature 2 and clinical observations indicating that relative platelet decline may have prognostic significance even above traditional TP thresholds. TP severity is classified as mild (100–149 ×10 9 /L), moderate (50–99 ×10 9 /L), severe (20–49 ×10 9 /L) and very severe (< 20 ×10 9 /L) 17,18 . TP is also classified according to timing: “IT (Initial thrombocytopenia)” is defined as thrombocytopenia present upon admission to the ICU; “ICU-TP (ICU-acquired thrombocytopenia)” is defined as thrombocytopenia developing during the ICU stay; “AT (Any thrombocytopenia)” is defined as all thrombocytopenia present at admission and/or during ICU stay. Duration-based TP is classified as Persistent (≥ 3 days) or Transient (< 3 days) 8 . Patients who died early may not have had sufficient time to develop persistent TP, which may have created survival bias in time-based analyses. Bleeding events were graded according to World Health Organization criteria 19 . Sepsis was defined using Sepsis-3 criteria 12 . Acute kidney injury (AKI) was defined according to KDIGO guidelines 20 . Acute liver injury (ALI) and Acute liver failure (ALF) were defined as previously described 21 , 22 . Disseminated Intravascular Coagulation (DIC) was defined based on International Society of Thrombosis and Haemostasis Scientific and Standardization Committee criteria 23 . Blood and blood product transfusions followed current international guidelines 24 – 25 . Heparin-induced thrombocytopenia (HIT) was assessed using the 4T clinical probability score 26 . Outcome s: The primary outcome was the relationship between the presence, timing (at the time of admission or onset during the course), and duration (≥ 3 days or less) of TP and mortality in the ICU and the relationship between STP/RTP and ICU mortality. Secondary outcomes included the relationship between TP severity and ICU, hospital, 28, and 90 day mortality, and the relationship between TP and bleeding, thrombotic events and transfusion requirements. Statistical Analysis Statistical analyses were performed using IBM SPSS Statistics for Windows, Version 27.0 (IBM Corp., Armonk, NY, USA). Normality was assessed visually (histograms and Q–Q plots) and using the Shapiro–Wilk test. Continuous variables were expressed as mean±standard deviation or median (interquartile range), as appropriate. Student’s t-test or Mann–Whitney U test was used for group comparisons. Categorical variables were analyzed using Pearson’s chi-square or Fisher’s exact tests. Comparisons across TP severity groups were performed using the Kruskal–Wallis test. To evaluate whether thrombocytopenia was independently associated with ICU mortality, a series of prespecified multivariable logistic regression models were constructed. Variables with p < 0.20 in univariate analyses and those considered clinically relevant were entered into the multivariable models. To minimize collinearity and avoid circularity, the SOFA score was excluded from multivariable modeling because platelet count constitutes one of its components. Age was not included as a separate covariate, as it is embedded within the APACHE II score. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported. Model discrimination was quantified using the area under the receiver operating characteristic curve (AUC), whereas model calibration was evaluated using the Hosmer–Lemeshow goodness-of-fit test. Optimal threshold values for TP in predicting ICU mortality were determined using the Youden index. A two-tailed p value < 0.05 was considered statistically significant. There were no missing data for the primary outcome. Results Study Population A total of 280 patients were included in the study. The median age of the cohort was 72 years (IQR 61–82). At ICU admission, the median GCS score was 13 (IQR 10–15), APACHE-II score was 21 (IQR 15–29), and SOFA score was 5 (IQR 3–8). Sepsis was present in 165 patients (58.9%). The most common comorbidities were hypertension, diabetes mellitus, and chronic kidney disease. ICU mortality was 33.9%, while hospital, 28-day, and 90-day mortality rates were 38.9%, 31.8%, and 42.5%, respectively. The median ICU and hospital lengths of stay (LOS) were 5 (IQR 3–10) and 11 (IQR 7–26) days. Detailed baseline characteristics of the study population are presented in Table 1. When evaluating the aetiologies of TP in the ICU, an average of 1.52 contributing causes per AT patient were identified. The most common cause was sepsis (73.7%), followed by DIC (28%), hemodilution (12.7%), bleeding (12.7%), drug-induced thrombocytopenia (7.6%), HIT (4.2%), other causes (trauma, malnutrition, vitamin deficiency) (10%), and unknown causes (3.3%). Comparison According to the Presence of Thrombocytopenia The baseline clinical characteristics, outcomes, and laboratory findings of the study population according to the presence of TP are presented in Table 2. Patients with TP were in a more severe clinical condition upon admission to the ICU and had significantly lower GCS scores and higher APACHE-II and SOFA scores compared to patients without TP (all p<0.001). Mortality outcomes in the TP group were higher: ICU mortality (53.4% vs. 19.8%), hospital mortality (59.3% vs. 24.1%), 28-day mortality (48.3% vs. 19.8%), and 90-day mortality (63.6% vs. 27.2%) (all p<0.001). Patients with TP also spent a longer time in ICU (p<0.001), but there was no significant difference in hospital stay between the groups. In terms of laboratory findings, lymphocyte counts, haemoglobin levels, and fibrinogen concentrations were significantly lower in thrombocytopenic patients, while AST, LDH, total bilirubin, creatinine, INR, D-dimer, lactate, and procalcitonin levels were significantly higher compared to non-thrombocytopenic patients. No significant differences were observed between the two groups in terms of age, gender distribution, neutrophil count, ALT levels, NLR, pH, or CRP levels. ROC Curve Analysis of Platelet Count for Predicting ICU Mortality Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory ability of platelet count (PC) for predicting ICU mortality (Figure 2). The area under the curve (AUC) was 0.583 (95% CI, 0.508–0.657; p=0.023), indicating a limited discriminative performance. Using the Youden index, the optimal PC cut-off value for predicting ICU mortality was identified as 205.5 ×10⁹/L, which provided a sensitivity of 50% and a specificity of 56%. In comparison, the conventional TP threshold of 150 ×10⁹/L demonstrated higher specificity (85%) but markedly lower sensitivity (34%). Similarly, the relative thrombocytopenia threshold of 200 ×10⁹/L showed a more balanced diagnostic performance, with a sensitivity of 47% and specificity of 59%, compared with the conventional thrombocytopenia threshold. Relative Thrombocytopenia Clinical features, outcomes, transfusion requirements, and complications according to the presence of RTP are presented in Table 3. Patients with RTP demonstrated significantly lower GCS scores and higher APACHE-II and SOFA scores compared to patients without RTP, indicating more severe disease at the time of admission to the ICU (p=0.043, p=0.002, and p<0.001, respectively). ICU mortality was significantly higher in the RTP group (38.3% vs. 23.8%, p=0.019), but hospital, 28-day and 90-day mortality rates did not differ significantly between groups. Patients with RTP required platelet transfusion and FFP/cryoprecipitate transfusion more frequently than those without RTP (p=0.002 and p=0.001, respectively), but red blood cell transfusion rates were similar between groups. Furthermore, the need for mechanical ventilation and vasopressor support was significantly higher in patients with RTP (p=0.006 and p<0.001, respectively). In terms of complications, DIC and AKI were significantly more prevalent in patients with RTP (p<0.001 and p=0.013, respectively) Impact of Thrombocytopenia Duration on Mortality The impact of TP/RTP duration on mortality outcomes is presented in Table 4. Patients with TP lasting ≥3 days had significantly higher ICU, hospital, and 90-day mortality rates compared with those with TP lasting <3 days. Specifically, prolonged TP was associated with increased ICU mortality (56% vs. 32.3%, OR 2.6, 95% CI 1.1–6.4, p=0.026), hospital mortality (64% vs. 35.5%, OR 3.2, 95% CI 1.3–7.7, p=0.007), and 90-day mortality (69.3% vs. 38.7%, OR 3.5, 95% CI 1.49–8.5, p=0.003). Although 28-day mortality was higher in patients with prolonged TP, the difference did not reach statistical significance (p=0.055). In contrast, the duration of RTP was not significantly associated with ICU, hospital, 28-day, or 90-day mortality. Association Between Thrombocytopenia Severity and Mortality The relationship between the severity of TP and mortality outcomes is presented in Table 5. Mortality rates increased progressively as the severity of TP increased. ICU mortality rose from 27.3% in patients with mild TP to 40.9% in patients with moderate TP and increased significantly in patients with severe and very severe TP (84% and 90.9%, respectively; p<0.001). A similar trend was observed in hospital mortality; the mortality rate, which was 33.3% in patients with mild TP, increased to 52.3% in patients with moderate TP and reached 84% and 90.9% in the severe and very severe TP groups (p<0.001). Likewise, 28-day and 90-day mortality rates also increased significantly with greater TP severity (p=0.006 and p<0.001, respectively), demonstrating a stepwise relationship between TP severity and adverse clinical outcomes. Comparison Between Initial and ICU-Acquired Thrombocytopenia A comparison of demographic, clinical, and laboratory characteristics between patients with thrombocytopenia at ICU admission (IT) and those who developed thrombocytopenia during ICU stay (ICU-TP) is presented in Table 6. There were no significant differences between the two groups regarding age, sex distribution, GCS score, APACHE-II score, or SOFA score. Similarly, ICU, hospital, 28-day, and 90-day mortality rates were comparable between the groups. However, TP lasting ≥3 days was significantly more common in the IT group compared with the ICU-TP group (87.5% vs. 52%, p<0.001). Patients with IT also had a longer hospital LOS than those with ICU-TP (p=0.049). Regarding laboratory parameters, patients who developed TP during ICU stay had significantly higher WBC and neutrophil counts, as well as higher lactate levels compared with patients with TP at admission. In contrast, lymphocyte counts and platelet counts were lower in the IT group. Other laboratory parameters, including haemoglobin, liver enzymes, bilirubin, creatinine, coagulation markers, and inflammatory markers, were similar between the two groups. Transfusion Requirements, Complications and Clinical Interventions The comparison of transfusion requirements, complications, and clinical interventions between patients with any thrombocytopenia (AT) and those who never developed thrombocytopenia (NT) is presented in Table 7. Patients with TP required significantly more platelet transfusions, RBC transfusions, and FFP/cryoprecipitate transfusions compared with patients without TP (all p<0.001). Regarding complications, sepsis, DIC, AKI, and acute liver injury were significantly more frequent in the TP group (all p<0.01). However, the rates of hemorrhage and thrombosis were similar between the groups. Patients with TP also required more intensive clinical support, including RRT, MV, and vasopressor therapy (all p<0.001). In addition, steroid therapy and CVC placement were significantly more common in patients with TP. In contrast, thromboprophylaxis practices and antibiotic therapy did not differ significantly between the groups. Multivariable Analysis Multivariable logistic regression analyses were performed to identify independent predictors of ICU mortality is presented in Table 8. In Model 1, TP was independently associated with increased ICU mortality (aOR 2.75, 95% CI 1.5–5, p=0.001). Higher APACHE-II scores (aOR 1.08, 95% CI 1.04–1.12, p<0.001) and the presence of sepsis (aOR 5.50, 95% CI 2.7–11.5, p<0.001) were also significant predictors. In Model 2, which additionally included clinical interventions, the requirement for mechanical ventilation emerged as the strongest predictor of ICU mortality (aOR 107.79, 95% CI 31.5–368.7, p<0.001), while sepsis remained independently associated with mortality. In this model, TP was not significantly associated with ICU mortality. In Model 3, DIC was strongly associated with ICU mortality (aOR 15, 95% CI 5.1–46.4, p<0.001). APACHE-II score and sepsis also remained independent predictors, whereas TP showed a borderline association with ICU mortality. Overall, sepsis and disease severity consistently remained independent predictors of ICU mortality across all models. Discussion Main findings In this single-centre prospective cohort study, we comprehensively evaluated the clinical significance of thrombocytopenia (TP) in critically ill patients by examining the presence, severity, duration, and temporal distribution of TP during the intensive care unit (ICU) stay. Below is a summary of the key findings of our study. Firstly, ICU, hospital, 28-day and 90-day mortality rates were significantly higher in critically ill patients with TP. Secondly, there was a stepwise correlation between the degree of TP and mortality; mortality progressively increased in patients with severe and very severe TP. Thirdly, significantly worse outcomes were associated with prolonged TP (≥ 3 days), suggesting that the persistence of TP may have important prognostic consequences. Finally, although the duration of Relative Thrombocytopenia (RTP) was associated with increased disease severity and increased need for organ support, it was not independently associated with mortality outcomes except in ICU. Thrombocytopenia as a marker of disease severity TP should be considered not only as a laboratory finding but also as an indicator of disease severity and organ dysfunction. This view is reinforced by the fact that patients with TP have lower GCS scores, higher SOFA and APACHE-II scores, increased use of organ support therapies such as vasopressors and RRT/MV, and significantly higher intensive care, hospital, 28-day and 90-day mortality rates. Large international cohorts also interpret the relationship between TP and mortality within the framework that, in most cases, TP is not a “cause” but a “reflection of disease burden and systemic inflammation” 18 . Coagulation disturbance and tissue hypoperfusion Our findings indicate that markers reflecting coagulopathy and tissue hypoperfusion, including increased INR, decreased fibrinogen levels, elevated D-dimer, and elevated lactate, were more markedly altered in patients with TP. This pattern supports consumption-related mechanisms, which are frequently observed in critically ill patients, particularly in the context of sepsis and DIC. Recent evidence suggests that platelets play roles beyond haemostasis, contributing to immune regulation, inflammatory responses, and interactions between the endothelium and leukocytes. Therefore, TP in sepsis likely reflects not only platelet consumption but also the complex interplay between inflammation, coagulation, and endothelial dysfunction². Inflammatory markers In our study, commonly utilized inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) 28 , exhibited no significant differences between patients with and without thrombocytopenia. While these indices are commonly employed as indicators of systemic inflammation in critically ill patients, they may exhibit reduced sensitivity to the complex mechanisms driving platelet consumption and destruction in the ICU environment. Likewise, the AST/ALT ratio was moderately elevated in patients with TP. High AST/ALT ratios in very sick patients are often seen as signs of systemic stress, low blood flow, or extrahepatic AST release, not just liver cell damage 29 . These results indicate that standard inflammatory indices may inadequately reflect the intricate inflammatory and coagulopathic mechanisms linked to thrombocytopenia in critically ill patients. Duration of thrombocytopenia Our findings regarding the prognostic significance of TP duration are particularly valuable: an increase in mortality was observed in cases of TP lasting ≥ 3 days. This is consistent with recent multicohort analyses supporting the concept of “persistent/chronic sepsis-associated thrombocytopenia”; it has been shown that the risk of poor outcomes increases as the duration prolongs 8 . Clinically, this result suggests that in ICU monitoring, the trend and rate of recovery may be more meaningful than a single platelet count (PC). On the other hand, the fact that no significant difference in mortality was observed between the presence of TP at admission ICU and its development during the course of treatment emphasizes that “developing TP is at least as important as TP at admission” in clinical practice. This finding supports the interpretation that TP may be a dynamic marker that emerges as systemic inflammation and organ failure worsen during the course of ICU. Platelet thresholds and relative thrombocytopenia The definition of thrombocytopenia varies considerably across the literature, and no universally accepted diagnostic threshold exists. While most studies define TP using an absolute platelet count < 150×10⁹/L, other thresholds and relative platelet decline criteria have also been proposed. When absolute PCs are used, a wide range of threshold values has been reported, including 200×10 9 /L, 150×10 9 /L, 80×10 9 /L and 60×10 9 /L. Similarly, studies based on platelet decline have applied reductions of > 30% or > 50% as diagnostic thresholds 2 . Nevertheless, in contemporary clinical practice and in the majority of published studies, TP is most commonly defined as an absolute PC < 150×10 9 /L 11 . In our study, the modest discriminatory performance of PC in predicting ICU mortality (AUC = 0.58) indicates that PC alone is a weak prognostic marker. Although it is a weak independent predictor in organ failure modeling (due to the heavy dominance of the need for mechanical ventilation in model calibration), we also found that it is weakly associated with mortality when evaluated with DIC These findings indicate that TP may function both as a marker of critical illness severity and as a component of the complex inflammatory and coagulative cascade underlying mortality in ICU patients. Specifically, the higher optimal threshold value (< 200×10 9 /L) determined using the Youden index suggests that clinically meaningful platelet decline may occur earlier and with relatively smaller decreases than those captured by the traditional < 150×10 9 /L threshold. Although PC < 200×10 9 /L does not meet the official definition of TP, it has been defined as “Relative Thrombocytopenia” 30 to facilitate the early diagnosis of high-risk patients. Although RTP is not associated with mortality (in our study, it was associated with ICU mortality), we propose the definition of “Subthreshold TP” for ICU patients as an early indicator of disease severity and recommend further studies. However, these findings may be influenced by center-specific characteristics, patient case diversity, and timing of measurement, and therefore require external validation. Steroid and antibiotic therapy Corticosteroid use was more frequent among patients with TP. This finding likely reflects greater disease severity rather than a direct effect of corticosteroids on PCs. In critically ill patients, corticosteroids are commonly administered in the context of septic shock, refractory hypotension, or severe systemic inflammation 12 clinical scenarios that are themselves strongly associated with TP. Similarly, antibiotic use was highly prevalent in both groups and did not differ significantly between patients with and without TP. While certain antibiotics have been implicated in drug-induced thrombocytopenia, such effects are relatively uncommon and often difficult to distinguish from sepsis-related platelet consumption in critically ill patients 31 . In this context, the lack of a significant association between antibiotic therapy and TP supports the interpretation that TP in our cohort predominantly reflects underlying disease processes rather than antibiotic exposure per se. Transfusion and complications In terms of transfusion and complications, the higher use of blood and blood products in the TP group Patients with TP required significantly more blood and blood product transfusions. However, the absence of a significant difference in bleeding complications between groups may be related to our patient selection criteria and the restrictive transfusion strategies used in our centre. Current intensive care guidelines support a shift from “routine practices” to evidence-based, more restrictive strategies based on clinical context in transfusion decisions for critically ill patients without bleeding 24 . We believe that the real-world data from your study provides valuable insight into how TP affects transfusion decisions and invasive procedure planning in the clinical setting. Strengths and Limitations of the Study Several limitations of this study should be acknowledged. Its single-center design may limit the generalizability of the findings and the exclusion of certain patient groups, such as those with end stage cirrhosis or uncontrolled major bleeding, may have influenced the observed associations. As a single-center observational study, residual confounding and selection bias cannot be completely excluded, despite the prospective design and systematic data collection. in septic patients, sepsis was accepted as the primary etiology of TP and platelet consumption and increased destruction were simultaneously considered as underlying mechanisms. While this approach reflects routine clinical practice in the ICU, it may have led to overlapping etiological and mechanistic classifications and limited causal interpretation regarding specific pathways. Nevertheless, a comprehensive assessment of clinical and laboratory variables, along with detailed subgroup analyses based on thrombocytopenia severity, persistence, and timing, strongly emphasizes the clinical significance of TP and RTP (Subthreshold TP) in medical intensive care settings. Conclusion Thrombocytopenia is prevalent among critically ill patients and is strongly correlated with disease severity, organ dysfunction, and mortality. Our findings highlight that not only the presence but also the severity and persistence of thrombocytopenia carry important prognostic information. Additionally, a decrease in platelets beyond the standard thrombocytopenia threshold may indicate an early sign of clinical worsening. These observations support the interpretation of thrombocytopenia as a dynamic biomarker of critical illness rather than merely a laboratory abnormality. Future multicentre studies are needed to validate the concept of subthreshold thrombocytopenia and to clarify its potential role in early risk stratification in ICU patients. Abbreviations ALI Acute Liver Injury ALF Acute Liver Failure AKI Acute Kidney Injury APACHE-II Acute Physiology and Chronic Health Evaluation II AT Any Thrombocytopenia CBC Complete Blood Count CVC Central Venous Catheter DIC Disseminated Intravascular Coagulation FFP Fresh Frozen Plasma GCS Glaskow Coma Scale HIT Heparin-induced thrombocytopenia ICU Intensive Care Unit ICU-TP ICU Acquired Thrombocytopenia IT Initial Thrombocytopenia LMWH Low Molecular Weight Heparin MV Mechanical Ventilation NT Never Thrombocytopenia PC Platelet Counts (PC) RBC Red Blood Cell RRT Renal Replacement Therapy; RTP Relative Thrombocytopenia STP Subthreshold thrombocytopenia TP Thrombocytopenia VP Vasopressor WBC White Blood Cell Declarations Ethical approval and consent to participate The study is based on the ICU cohort of the Kayseri City Hospital which consists: A prospective cohort starting in September 2023 and August 2024. The Ethics Committee approval for the ICU cohort is dated July 25, 2023, and numbered 877. It was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent Data availability statement: The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Author Contributions (CRediT Statement) : Kamil Deveci : Writing–review&editing, Writing–original draft, Data curation, Project administration, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization, Supervision. Maruf Boran: Writing–review&editing, Supervision, Methodology, Formal analysis, Data curation, Conceptualization. Kübra E. Bahar: Writing–review&editing, Supervision, Resources, Methodology, Formal analysis, Data curation, Conceptualization. Fatma Sarıdağ: Writing–review&editing, Supervision, Resources, Methodology, Formal analysis, Data curation, Conceptualization Acknowledgements: During the preparation of this work the authors used ChatGPT (OpenAI) and NotebookLM in order to English language editing and stylistic improvement. After using this tool, the authors reviewed and edited the content as needed and takes full responsibility for the content of the published article. References Pène F, Russell L, Aubron C. Thrombocytopenia in the intensive care unit: diagnosis and management. Ann Intensive Care. 2025;15(1):25. Published 2025 Feb 22. doi:10.1186/s13613-025-01447-x Jonsson AB, Rygård SL, Hildebrandt T, Perner A, Møller MH, Russell L. Thrombocytopenia in intensive care unit patients: A scoping review. Acta Anaesthesiol Scand. 2021;65(1):2-14. doi:10.1111/aas.13699 Anthon CT, Pène F, Perner A, et al. Platelet transfusions in adult ICU patients with thrombocytopenia: A sub-study of the PLOT-ICU inception cohort study. Acta Anaesthesiol Scand. 2024;68(8):1018-1030. doi:10.1111/aas.14467 Ostadi Z, Shadvar K, Sanaie S, Mahmoodpoor A, Saghaleini SH. Thrombocytopenia in the intensive care unit. Pak J Med Sci. (2019) 35:282–7. doi: 10.12669/pjms.35.1.19 Menard CE, Kumar A, Houston DS, et al. Evolution and Impact of Thrombocytopenia in Septic Shock: A Retrospective Cohort Study. Crit Care Med. 2019;47(4):558-565. doi:10.1097/CCM.0000000000003644 Thiele T, Selleng K, Selleng S, Greinacher A, Bakchoul T. Thrombocytopenia in the intensive care unit-diagnostic approach and management. Semin Hematol. 2013;50(3):239-250. doi:10.1053/j.seminhematol.2013.06.008 Thiolliere F, Serre-Sapin AF, Reignier J, et al. Epidemiology and outcome of thrombocytopenic patients in the intensive care unit: results of a prospective multicenter study. Intensive Care Med. 2013;39(8):1460-1468. doi:10.1007/s00134-013-2963-3 Zhang W, Cheng X, Cai X, Zhang Z, Jiang X. Prognostic impact of persistent versus transient sepsis-associated thrombocytopenia in multicohort data. iScience. 2025;28(12):114023. Published 2025 Nov 11. doi:10.1016/j.isci.2025.114023 Williamson DR, Lesur O, Tetrault JP, Nault V, Pilon D. Thrombocytopenia in the critically ill: Prevalence, incidence, risk factors, and clinical outcomes. Canadian 29 Journal of Anesthesia 2013; 60: 641-51 Ben Hamida C, Lauzet JY, Rezaiguia-Delclaux S, Duvoux C, Cherqui D, Duvaldestin P, Stephan F. Effect of severe thrombocytopenia on patient outcome after 3 liver transplantation. Intensive Care Med 2003; 29: 756-62 Thachil J, Warkentin TE. How do we approach thrombocytopenia in critically ill patients?. Br J Haematol. 2017;177(1):27-38. doi:10.1111/bjh.14482 Singer M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287 Kumar A, Mhaskar R, Grossman BJ, Kaufman RM, Tobian AAR, Kleinman S, Gernsheimer T, Tinmouth AT, Djulbegovic B, Panel APTG. Platelet transfusion: a systematic review of the clinical evidence. Transfusion 2015; 55: 1116-27 de Bruin S, Scheeren TWL, Bakker J, van Bruggen R, Vlaar APJ; Cardiovascular Dynamics Section and Transfusion Guideline Task Force of the ESICM. Transfusion practice in the non-bleeding critically ill: an international online survey-the TRACE survey. Crit Care. 2019;23(1):309. Published 2019 Sep 11. doi:10.1186/s13054-019-2591-6 Vanderschueren S, De Weerdt A, Malbrain M, et al. Thrombocytopenia and prognosis in intensive care. Crit Care Med. 2000;28(6):1871-1876. doi:10.1097/00003246-200006000-00031 von Elm E, Altman DG, Egger M, Pocock SJ, Gøtzsche PC, Vandenbroucke JP; STROBE Initiative. Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: guidelines for reporting observational studies. BMJ. 2007 Oct 20;335(7624):806-8. doi: 10.1136/bmj.39335.541782.AD. PMID: 17947786; PMCID: PMC2034723. Williamson DR, Albert M, Heels-Ansdell D, et al; PROTECT collaborators, the Canadian Critical Care Trials Group, and the Australian and New Zealand Intensive Care Society Clinical Trials Group. Thrombocytopenia in critically ill patients receiving thromboprophylaxis: frequency, risk factors, and outcomes. Chest. 2013;144(4):1207-1215 Anthon CT, Pène F, Perner A, et al. Thrombocytopenia and platelet transfusions in ICU patients: an international inception cohort study (PLOT-ICU). Intensive Care Med. 2023;49(11):1327-1338. doi:10.1007/s00134-023-07225-2 World Health Organization. WHO handbook for reporting results of cancer treatment. Geneva: World Health Organization; 1979. WHO Offset Publication No. 48. Khwaja A. KDIGO clinical practice guidelines for acute kidney injury. Nephron Clin Pract. 2012;120(4):c179-c184. doi:10.1159/000339789 Fernández J, Bassegoda O, Toapanta D, Bernal W. Acute liver failure: A practical update. JHEP Rep. 2024;6(9):101131. Published 2024 Jun 10. doi:10.1016/j.jhepr.2024.101131 European Association for the Study of the Liver. Electronic address: [email protected] ; Clinical practice guidelines panel, Wendon, J, et al. EASL Clinical Practical Guidelines on the management of acute (fulminant) liver failure. J Hepatol. 2017;66(5):1047-1081. doi:10.1016/j.jhep.2016.12.003 Toh CH, Alhamdi Y, Abrams ST. Current Pathological and Laboratory Considerations in the Diagnosis of Disseminated Intravascular Coagulation. Ann Lab Med. 2016;36(6):505-512. doi:10.3343/alm.2016.36.6.505 Vlaar AP, Oczkowski S, de Bruin S, et al. Transfusion strategies in non-bleeding critically ill adults: a clinical practice guideline from the European Society of Intensive Care Medicine. Intensive Care Med. 2020;46(4):673-696. doi:10.1007/s00134-019-05884-8 Møller MH, Sigurðsson MI, Olkkola KT, Rehn M, Yli-Hankala A, Chew MS. Transfusion strategies in bleeding critically ill adults: A clinical practice guideline from the European Society of Intensive Care Medicine: Endorsement by the Scandinavian Society of Anaesthesiology and Intensive Care Medicine. Acta Anaesthesiol Scand. 2022;66(5):638-639. doi:10.1111/aas.14047 Cuker A, Arepally GM, Chong BH, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv. 2018;2(22):3360-3392. doi:10.1182/bloodadvances.2018024489 Setarehaseman A, Mohammadi A, Maitta RW. Thrombocytopenia in Sepsis. Life (Basel). 2025;15(2):274. Published 2025 Feb 11. doi:10.3390/life15020274 Liang P, Yu F. Value of CRP, PCT, and NLR in Prediction of Severity and Prognosis of Patients With Bloodstream Infections and Sepsis. Front Surg. 2022;9:857218. Published 2022 Mar 7. doi:10.3389/fsurg.2022.857218 Wang L, Jin P, Hui Y, et al. A non-linear association between AST/ALT ratio and 28-day mortality in critically ill elderly: evidence from a multicenter study. Sci Rep. 2025;15(1):25831. Published 2025 Jul 16. doi:10.1038/s41598-025-11220-6 Kutcher ME, Cripps MW, McCreery RC, et al. Criteria for empiric treatment of hyperfibrinolysis after trauma. J Trauma Acute Care Surg. 2012;73(1):87-93. doi:10.1097/TA.0b013e3182598c70 Priziola JL, Smythe MA, Dager WE. Drug-induced thrombocytopenia in critically ill patients. Crit Care Med. 2010;38(6 Suppl):S145-S154. doi:10.1097/CCM.0b013e3181de0b88 Tables Tables 1 to 8 are available in the Supplementary Files section. Additional Declarations No competing interests reported. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-9178594","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":623465012,"identity":"5d49e410-c1ff-411d-9fd2-9d6ea9897823","order_by":0,"name":"Kamil Deveci","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA50lEQVRIiWNgGAWjYBACCSA+8IANxGRsfAAkefiI0pIA0dJsANLCRowWBogWBjYwh6AWyfbTiQcSymwS+9kPt1V+zbGTYWNgfvjoBh4t0jy5Gw4knEtLnNmT2HZbdlsy0GFsxsY5eLTIMQC1JLYdNja4wdh2W3IbM1ALD5s0Xi38b0Fa/hvbA7UUS26rJ6xFWgJsywE5AwnGNsaP2w4T1iI54y3IL8lyEmcSm6UZtx3nYWMm4BeJ87mbP3wos+Phbz/+8OPPbdX2/OzNDx/j04ICmHnAJLHKQYDxBymqR8EoGAWjYMQAAJE9SNv4NAvjAAAAAElFTkSuQmCC","orcid":"","institution":"Kayseri City Education and Research Hospital","correspondingAuthor":true,"prefix":"","firstName":"Kamil","middleName":"","lastName":"Deveci","suffix":""},{"id":623465013,"identity":"51e63622-9c8d-414a-a229-2710cb3d8eab","order_by":1,"name":"Maruf Boran","email":"","orcid":"","institution":"Kayseri City Education and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Maruf","middleName":"","lastName":"Boran","suffix":""},{"id":623465014,"identity":"2e951fba-3512-43b5-9216-5c284f7fe1b1","order_by":2,"name":"Kübra E. Bahar","email":"","orcid":"","institution":"Kayseri City Education and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Kübra","middleName":"E.","lastName":"Bahar","suffix":""},{"id":623465015,"identity":"938c94b3-b290-4512-8d02-82f5ae1e5446","order_by":3,"name":"Fatma Sarıdağ","email":"","orcid":"","institution":"Kayseri City Education and Research Hospital","correspondingAuthor":false,"prefix":"","firstName":"Fatma","middleName":"","lastName":"Sarıdağ","suffix":""}],"badges":[],"createdAt":"2026-03-20 11:53:13","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-9178594/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-9178594/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":107483622,"identity":"e87ca628-212f-4ac2-8f82-6e7143508b63","added_by":"auto","created_at":"2026-04-22 02:28:31","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":115184,"visible":true,"origin":"","legend":"\u003cp\u003ePatient Flow Diagram\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-9178594/v1/e35eb7a4772aa9151c5e6ffc.png"},{"id":107257180,"identity":"68d172d1-3e84-4915-8137-f53a71ad0eb6","added_by":"auto","created_at":"2026-04-19 12:26:29","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":45535,"visible":true,"origin":"","legend":"\u003cp\u003ePredictive Performance of Platelet Count for ICU mortality assessed by ROC curve analysis\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-9178594/v1/307b7396e07d908eaa800c4a.png"},{"id":107486180,"identity":"de662441-eba8-4cf5-a6ae-d9f988614efa","added_by":"auto","created_at":"2026-04-22 02:37:39","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":600713,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-9178594/v1/e517571e-5191-457a-b484-6b5f4d236d7b.pdf"},{"id":107257178,"identity":"75ed7fc1-e099-4079-b382-14f58c228f14","added_by":"auto","created_at":"2026-04-19 12:26:29","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":44571,"visible":true,"origin":"","legend":"","description":"","filename":"Tables.docx","url":"https://assets-eu.researchsquare.com/files/rs-9178594/v1/0fb3b5f96e1f30022e72a178.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"The Prognostic Impact of the Platelet Dynamics and Subthreshold Thrombocytopenia in Intensive Care Patients: A Prospective Cohort Study","fulltext":[{"header":"Background","content":"\u003cp\u003ePlatelets are short-lived, nucleated blood components that play an important role in haemostasis as well as in immune regulation, inflammation and endothelial interaction\u003csup\u003e\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e\u003c/sup\u003e. A decrease in platelet count (PC) is defined as thrombocytopenia (TP), and although previous publications have used different threshold values (\u0026le;\u0026thinsp;200 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, \u0026le;\u0026thinsp;80 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, \u0026le;\u0026thinsp;60 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) and rates of decrease (\u0026lt;\u0026thinsp;30%, 50%)\u003csup\u003e2\u003c/sup\u003e, current literature defines TP as a PC below 150 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003csup\u003e3\u003c/sup\u003e. It is quite common in intensive care units (ICUs); reported prevalence rates vary considerably across studies (8\u0026ndash;56%)\u003csup\u003e2\u0026ndash;4\u003c/sup\u003e. Many causes of TP, such as sepsis, medications, trauma, and haemodilution, may coexist in critically ill patients\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e\u003c/sup\u003e. Among these aetiologies, sepsis remains the most important cause of TP in the ICU and has led to the widespread use of the term \u0026ldquo;sepsis-associated thrombocytopenia\u0026rdquo; in the literature\u003csup\u003e\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e,\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTP increases the risk of bleeding, length of stay (LOS) in the ICU/hospital, and the need for life support devices, vasopressors, and mortality \u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e,\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u003c/sup\u003e. A linear relationship has been found between the severity of TP and mortality and disease severity\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e,\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. Moreover TP lasting longer than three days has been associated with poor prognosis and mortality\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Particularly in severe TP, fear of bleeding leads to delay in invasive procedures, postponement of prophylactic anticoagulation, and platelet transfusions\u003csup\u003e\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e,\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e,\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e. Correcting one factor in the treatment of TP patients may not always lead to clinical improvement\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e. The most important aspect of treatment is to correct the underlying disease, if possible.\u003c/p\u003e \u003cp\u003eTP may be present at admission to the ICU or may develop during the course of treatment. The development of TP should be considered a consequence of the severity of the disease and the critical condition\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e. Therefore, monitoring the course of PC and the duration of TP is important in clinical follow-up.\u003c/p\u003e \u003cp\u003eOur primary objective was to evaluate the prognostic impact of platelet dynamics, including the presence, timing, and duration of TP in the ICU, on mortality and clinical outcomes, and to investigate whether there is a relationship between platelet counts below 200 x 10⁹/L (subthreshold thrombocytopenia) and clinical outcomes.\u003c/p\u003e"},{"header":"Patients and methods","content":"\u003cp\u003e\u003cb\u003eStudy Population\u003c/b\u003e: This observational prospective cohort study was conducted in accordance with the STROBE Statement\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e for cohort studies. The study was conducted at Medical Intensive Care Unit-3 of Kayseri City Education and Research Hospital in Kayseri, Turkey. All consecutive patients aged 18 years and older admitted to the ICU and followed for more than 24 hours were eligible for inclusion in the study and had no missing critical information (death, organ failure, need for life support devices, need for blood product replacement) in their records. Patients with known terminal-stage solid or haematological malignancies, patients undergoing active chemotherapy, patients with end-stage (Child-pugh class C) liver cirrhosis, and patients with uncontrolled bleeding during hospitalisation were excluded from the study at the outset because they were associated with platelet abnormalities, regardless of their critical illness status. Inclusion of such patients could confound platelet kinetics and outcome analyses (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). Of the 415 patients evaluated, 280 met the predefined inclusion criteria and were enrolled. Patients were followed until they were discharged from the hospital or for 90 days. The study was approved by the Institutional Ethics Committee (protocol number 2023\u0026ndash;877). Patient enrollment began in September 2023 and ended in August 2024. All methods were performed in accordance with the relevant guidelines and regulations, in line with the principles of the Declaration of Helsinki. All patients provided written informed consent.\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003cp\u003eDue to its single-centre design and predefined exclusion criteria, selection bias cannot be entirely eliminated, and the findings may not be generalisable to all ICU populations, particularly surgical or haematology-focused cohorts.\u003c/p\u003e \u003cp\u003e \u003cb\u003eStudy Procedure\u003c/b\u003e: Patient eligibility was assessed upon admission to the ICU. Patients who met the inclusion criteria were informed about the study and enrolled on the same day. In line with the study objectives, standard ICU management protocols were applied without modification.\u003c/p\u003e \u003cp\u003e \u003cstrong\u003eSample Size\u003c/strong\u003e \u003cp\u003eA pre-trial sample size calculation was performed using G*Power (version 3.1). Assuming a two-tailed alpha value of 0.05, statistical power of 80%, and a 20% difference in mortality rates between patients with and without thrombocytopenia (40% vs. 20%), a minimum of 104 patients were required. The final cohort comprised 280 patients, significantly exceeding the estimated requirement and thus enhancing the statistical precision of the analyses.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eStudy Data\u003c/strong\u003e \u003cp\u003eClinical data were obtained from patient medical records and the hospital's electronic medical record system (KEYDATA). The variables collected included demographic characteristics, comorbidities, reason for admission to the ICU, disease severity scores, therapeutic interventions, transfusion requirements, laboratory parameters, and clinical outcomes. The APACHE-II Score was calculated based on the worst values recorded within the first 24 hours of admission to the ICU. The SOFA score was calculated based on the values at the time of admission to the ICU. Recorded therapeutic interventions included anticoagulant and corticosteroid use, vasopressor support (VS), central venous catheter (CVC) placement, mechanical ventilation (MV), renal replacement therapy (RRT), and transfusion data. Laboratory variables included complete blood count (CBC) parameters, biochemical markers, inflammatory markers, coagulation parameters, and arterial blood gas measurements. Platelet counts (PC) were measured using impedance-based analysers and verified by optical methods when necessary. Peripheral blood smears were examined when clinically indicated. Routine laboratory assessments were performed at least once daily as part of standard ICU monitoring.\u003c/p\u003e \u003c/p\u003e \u003cp\u003e \u003cstrong\u003eDefinitions\u003c/strong\u003e \u003cp\u003e \u003cem\u003eThrombocytopenia (TP)\u003c/em\u003e is defined as a PC\u0026thinsp;\u0026lt;\u0026thinsp;150 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. Relative Thrombocytopenia (RTP) or subthreshold thrombocytopenia (STP) is defined as PC\u0026thinsp;\u003cem\u003e\u0026lt;\u003c/em\u003e\u0026thinsp;200 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. The RTP threshold was selected based on previous literature\u003csup\u003e\u003cb\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/b\u003e\u003c/sup\u003e and clinical observations indicating that relative platelet decline may have prognostic significance even above traditional TP thresholds.\u003c/p\u003e \u003c/p\u003e \u003cp\u003eTP severity is classified as mild (100\u0026ndash;149 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), moderate (50\u0026ndash;99 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L), severe (20\u0026ndash;49 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) and very severe (\u0026lt;\u0026thinsp;20 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L)\u003csup\u003e17,18\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003eTP is also classified according to timing: \u0026ldquo;IT (Initial thrombocytopenia)\u0026rdquo; is defined as thrombocytopenia present upon admission to the ICU; \u0026ldquo;ICU-TP (ICU-acquired thrombocytopenia)\u0026rdquo; is defined as thrombocytopenia developing during the ICU stay; \u0026ldquo;AT (Any thrombocytopenia)\u0026rdquo; is defined as all thrombocytopenia present at admission and/or during ICU stay.\u003c/p\u003e \u003cp\u003eDuration-based TP is classified as Persistent (\u0026ge;\u0026thinsp;3 days) or Transient (\u0026lt;\u0026thinsp;3 days)\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Patients who died early may not have had sufficient time to develop persistent TP, which may have created survival bias in time-based analyses.\u003c/p\u003e \u003cp\u003e\u003cem\u003eBleeding\u003c/em\u003e events were graded according to World Health Organization criteria\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eSepsis\u003c/em\u003e was defined using Sepsis-3 criteria\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eAcute kidney injury (AKI)\u003c/em\u003e was defined according to KDIGO guidelines\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eAcute liver injury (ALI) and Acute liver failure (ALF)\u003c/em\u003e were defined as previously described\u003csup\u003e\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e,\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eDisseminated Intravascular Coagulation (DIC)\u003c/em\u003e was defined based on International Society of Thrombosis and Haemostasis Scientific and Standardization Committee criteria\u003csup\u003e\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e\u003c/sup\u003e. Blood and blood product \u003cem\u003etransfusions\u003c/em\u003e followed current international guidelines\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e. \u003cem\u003eHeparin-induced thrombocytopenia (HIT)\u003c/em\u003e was assessed using the 4T clinical probability score\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e.\u003c/p\u003e \u003cp\u003e \u003cb\u003eOutcome\u003c/b\u003es: The primary outcome was the relationship between the presence, timing (at the time of admission or onset during the course), and duration (\u0026ge;\u0026thinsp;3 days or less) of TP and mortality in the ICU and the relationship between STP/RTP and ICU mortality. Secondary outcomes included the relationship between TP severity and ICU, hospital, 28, and 90 day mortality, and the relationship between TP and bleeding, thrombotic events and transfusion requirements.\u003c/p\u003e \u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003eStatistical Analysis\u003c/h2\u003e \u003cp\u003eStatistical analyses were performed using IBM SPSS Statistics for Windows, Version 27.0 (IBM Corp., Armonk, NY, USA). Normality was assessed visually (histograms and Q\u0026ndash;Q plots) and using the Shapiro\u0026ndash;Wilk test. Continuous variables were expressed as mean\u0026plusmn;standard deviation or median (interquartile range), as appropriate. Student\u0026rsquo;s t-test or Mann\u0026ndash;Whitney U test was used for group comparisons. Categorical variables were analyzed using Pearson\u0026rsquo;s chi-square or Fisher\u0026rsquo;s exact tests. Comparisons across TP severity groups were performed using the Kruskal\u0026ndash;Wallis test. To evaluate whether thrombocytopenia was independently associated with ICU mortality, a series of prespecified multivariable logistic regression models were constructed. Variables with p\u0026thinsp;\u0026lt;\u0026thinsp;0.20 in univariate analyses and those considered clinically relevant were entered into the multivariable models. To minimize collinearity and avoid circularity, the SOFA score was excluded from multivariable modeling because platelet count constitutes one of its components. Age was not included as a separate covariate, as it is embedded within the APACHE II score. Adjusted odds ratios (aORs) with 95% confidence intervals (CIs) were reported. Model discrimination was quantified using the area under the receiver operating characteristic curve (AUC), whereas model calibration was evaluated using the Hosmer\u0026ndash;Lemeshow goodness-of-fit test. Optimal threshold values for TP in predicting ICU mortality were determined using the Youden index. A two-tailed p value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered statistically significant. There were no missing data for the primary outcome.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003e\u003cstrong\u003e\u003cem\u003eStudy Population\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA total of 280 patients were included in the study. The median age of the cohort was 72 years (IQR 61\u0026ndash;82). At ICU admission, the median GCS score was 13 (IQR 10\u0026ndash;15), APACHE-II score was 21 (IQR 15\u0026ndash;29), and SOFA score was 5 (IQR 3\u0026ndash;8). Sepsis was present in 165 patients (58.9%). The most common comorbidities were hypertension, diabetes mellitus, and chronic kidney disease. ICU mortality was 33.9%, while hospital, 28-day, and 90-day mortality rates were 38.9%, 31.8%, and 42.5%, respectively. The median ICU and hospital lengths of stay (LOS) were 5 (IQR 3\u0026ndash;10) and 11 (IQR 7\u0026ndash;26) days. Detailed baseline characteristics of the study population are presented in Table 1.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eWhen evaluating the aetiologies of TP in the ICU, an average of 1.52 contributing causes per AT patient were identified. The most common cause was sepsis (73.7%), followed by DIC (28%), hemodilution (12.7%), bleeding (12.7%), drug-induced thrombocytopenia (7.6%), HIT (4.2%), other causes (trauma, malnutrition, vitamin deficiency) (10%), and unknown causes (3.3%).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComparison According to the Presence of Thrombocytopenia\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe baseline clinical characteristics, outcomes, and laboratory findings of the study population according to the presence of TP are presented in Table 2. Patients with TP were in a more severe clinical condition upon admission to the ICU and had significantly lower GCS scores and higher APACHE-II and SOFA scores compared to patients without TP (all p\u0026lt;0.001). Mortality outcomes in the TP group were higher: ICU mortality (53.4% vs. 19.8%), hospital mortality (59.3% vs. 24.1%), 28-day mortality (48.3% vs. 19.8%), and 90-day mortality (63.6% vs. 27.2%) (all p\u0026lt;0.001). Patients with TP also spent a longer time in ICU (p\u0026lt;0.001), but there was no significant difference in hospital stay between the groups. In terms of laboratory findings, lymphocyte counts, haemoglobin levels, and fibrinogen concentrations were significantly lower in thrombocytopenic patients, while AST, LDH, total bilirubin, creatinine, INR, D-dimer, lactate, and procalcitonin levels were significantly higher compared to non-thrombocytopenic patients. No significant differences were observed between the two groups in terms of age, gender distribution, neutrophil count, ALT levels, NLR, pH, or CRP levels.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eROC Curve Analysis of Platelet Count for Predicting ICU Mortality\u003c/em\u003e\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eReceiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminatory ability of platelet count (PC) for predicting ICU mortality (Figure 2). The area under the curve (AUC) was 0.583 (95% CI, 0.508\u0026ndash;0.657; p=0.023), indicating a limited discriminative performance. Using the Youden index, the optimal PC cut-off value for predicting ICU mortality was identified as 205.5 \u0026times;10⁹/L, which provided a sensitivity of 50% and a specificity of 56%. In comparison, the conventional TP threshold of 150 \u0026times;10⁹/L demonstrated higher specificity (85%) but markedly lower sensitivity (34%). Similarly, the relative thrombocytopenia threshold of 200 \u0026times;10⁹/L showed a more balanced diagnostic performance, with a sensitivity of 47% and specificity of 59%, compared with the conventional thrombocytopenia threshold.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eRelative Thrombocytopenia\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eClinical features, outcomes, transfusion requirements, and complications according to the presence of RTP are presented in Table 3. Patients with RTP demonstrated significantly lower GCS scores and higher APACHE-II and SOFA scores compared to patients without RTP, indicating more severe disease at the time of admission to the ICU (p=0.043, p=0.002, and p\u0026lt;0.001, respectively). ICU mortality was significantly higher in the RTP group (38.3% vs. 23.8%, p=0.019), but hospital, 28-day and 90-day mortality rates did not differ significantly between groups. Patients with RTP required platelet transfusion and FFP/cryoprecipitate transfusion more frequently than those without RTP (p=0.002 and p=0.001, respectively), but red blood cell transfusion rates were similar between groups. Furthermore, the need for mechanical ventilation and vasopressor support was significantly higher in patients with RTP (p=0.006 and p\u0026lt;0.001, respectively). In terms of complications, DIC and AKI were significantly more prevalent in patients with RTP (p\u0026lt;0.001 and p=0.013, respectively)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eImpact of Thrombocytopenia Duration on Mortality\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe impact of TP/RTP duration on mortality outcomes is presented in Table 4. Patients with TP lasting \u0026ge;3 days had significantly higher ICU, hospital, and 90-day mortality rates compared with those with TP lasting \u0026lt;3 days. Specifically, prolonged TP was associated with increased ICU mortality (56% vs. 32.3%, OR 2.6, 95% CI 1.1\u0026ndash;6.4, p=0.026), hospital mortality (64% vs. 35.5%, OR 3.2, 95% CI 1.3\u0026ndash;7.7, p=0.007), and 90-day mortality (69.3% vs. 38.7%, OR 3.5, 95% CI 1.49\u0026ndash;8.5, p=0.003). Although 28-day mortality was higher in patients with prolonged TP, the difference did not reach statistical significance (p=0.055). In contrast, the duration of RTP was not significantly associated with ICU, hospital, 28-day, or 90-day mortality.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eAssociation Between Thrombocytopenia Severity and Mortality\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe relationship between the severity of TP and mortality outcomes is presented in Table 5. Mortality rates increased progressively as the severity of TP increased. ICU mortality rose from 27.3% in patients with mild TP to 40.9% in patients with moderate TP and increased significantly in patients with severe and very severe TP (84% and 90.9%, respectively; p\u0026lt;0.001). A similar trend was observed in hospital mortality; the mortality rate, which was 33.3% in patients with mild TP, increased to 52.3% in patients with moderate TP and reached 84% and 90.9% in the severe and very severe TP groups (p\u0026lt;0.001). Likewise, 28-day and 90-day mortality rates also increased significantly with greater TP severity (p=0.006 and p\u0026lt;0.001, respectively), demonstrating a stepwise relationship between TP severity and adverse clinical outcomes.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eComparison Between Initial and ICU-Acquired Thrombocytopenia\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA comparison of demographic, clinical, and laboratory characteristics between patients with thrombocytopenia at ICU admission (IT) and those who developed thrombocytopenia during ICU stay (ICU-TP) is presented in Table 6. There were no significant differences between the two groups regarding age, sex distribution, GCS score, APACHE-II score, or SOFA score. Similarly, ICU, hospital, 28-day, and 90-day mortality rates were comparable between the groups. However, TP lasting \u0026ge;3 days was significantly more common in the IT group compared with the ICU-TP group (87.5% vs. 52%, p\u0026lt;0.001). Patients with IT also had a longer hospital LOS than those with ICU-TP (p=0.049). Regarding laboratory parameters, patients who developed TP during ICU stay had significantly higher WBC and neutrophil counts, as well as higher lactate levels compared with patients with TP at admission. In contrast, lymphocyte counts and platelet counts were lower in the IT group. Other laboratory parameters, including haemoglobin, liver enzymes, bilirubin, creatinine, coagulation markers, and inflammatory markers, were similar between the two groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eTransfusion Requirements, Complications and Clinical Interventions\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe comparison of transfusion requirements, complications, and clinical interventions between patients with any thrombocytopenia (AT) and those who never developed thrombocytopenia (NT) is presented in Table 7. Patients with TP required significantly more platelet transfusions, RBC transfusions, and FFP/cryoprecipitate transfusions compared with patients without TP (all p\u0026lt;0.001). Regarding complications, sepsis, DIC, AKI, and acute liver injury were significantly more frequent in the TP\u0026nbsp;group (all p\u0026lt;0.01). However, the rates of hemorrhage and thrombosis were similar between the groups. Patients with TP also required more intensive clinical support, including RRT, MV, and vasopressor therapy (all p\u0026lt;0.001). In addition, steroid therapy and CVC placement were significantly more common in patients with TP. In contrast, thromboprophylaxis practices and antibiotic therapy did not differ significantly between the groups.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u003cem\u003eMultivariable Analysis\u003c/em\u003e\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMultivariable logistic regression analyses were performed to identify independent predictors of ICU mortality is presented in Table 8. In Model 1, TP was independently associated with increased ICU mortality (aOR 2.75, 95% CI 1.5\u0026ndash;5, p=0.001). Higher APACHE-II scores (aOR 1.08, 95% CI 1.04\u0026ndash;1.12, p\u0026lt;0.001) and the presence of sepsis (aOR 5.50, 95% CI 2.7\u0026ndash;11.5, p\u0026lt;0.001) were also significant predictors. In Model 2, which additionally included clinical interventions, the requirement for mechanical ventilation emerged as the strongest predictor of ICU mortality (aOR 107.79, 95% CI 31.5\u0026ndash;368.7, p\u0026lt;0.001), while sepsis remained independently associated with mortality. In this model, TP was not significantly associated with ICU mortality. In Model 3, DIC was strongly associated with ICU mortality (aOR 15, 95% CI 5.1\u0026ndash;46.4, p\u0026lt;0.001). APACHE-II score and sepsis also remained independent predictors, whereas TP showed a borderline association with ICU mortality. Overall, sepsis and disease severity consistently remained independent predictors of ICU mortality across all models.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e \u003ch2\u003eMain findings\u003c/h2\u003e \u003cp\u003eIn this single-centre prospective cohort study, we comprehensively evaluated the clinical significance of thrombocytopenia (TP) in critically ill patients by examining the presence, severity, duration, and temporal distribution of TP during the intensive care unit (ICU) stay. Below is a summary of the key findings of our study. Firstly, ICU, hospital, 28-day and 90-day mortality rates were significantly higher in critically ill patients with TP. Secondly, there was a stepwise correlation between the degree of TP and mortality; mortality progressively increased in patients with severe and very severe TP. Thirdly, significantly worse outcomes were associated with prolonged TP (\u0026ge;\u0026thinsp;3 days), suggesting that the persistence of TP may have important prognostic consequences. Finally, although the duration of Relative Thrombocytopenia (RTP) was associated with increased disease severity and increased need for organ support, it was not independently associated with mortality outcomes except in ICU.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec16\" class=\"Section2\"\u003e \u003ch2\u003eThrombocytopenia as a marker of disease severity\u003c/h2\u003e \u003cp\u003eTP should be considered not only as a laboratory finding but also as an indicator of disease severity and organ dysfunction. This view is reinforced by the fact that patients with TP have lower GCS scores, higher SOFA and APACHE-II scores, increased use of organ support therapies such as vasopressors and RRT/MV, and significantly higher intensive care, hospital, 28-day and 90-day mortality rates. Large international cohorts also interpret the relationship between TP and mortality within the framework that, in most cases, TP is not a \u0026ldquo;cause\u0026rdquo; but a \u0026ldquo;reflection of disease burden and systemic inflammation\u0026rdquo;\u003csup\u003e18\u003c/sup\u003e.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec17\" class=\"Section2\"\u003e \u003ch2\u003eCoagulation disturbance and tissue hypoperfusion\u003c/h2\u003e \u003cp\u003eOur findings indicate that markers reflecting coagulopathy and tissue hypoperfusion, including increased INR, decreased fibrinogen levels, elevated D-dimer, and elevated lactate, were more markedly altered in patients with TP. This pattern supports consumption-related mechanisms, which are frequently observed in critically ill patients, particularly in the context of sepsis and DIC. Recent evidence suggests that platelets play roles beyond haemostasis, contributing to immune regulation, inflammatory responses, and interactions between the endothelium and leukocytes. Therefore, TP in sepsis likely reflects not only platelet consumption but also the complex interplay between inflammation, coagulation, and endothelial dysfunction\u0026sup2;.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec18\" class=\"Section2\"\u003e \u003ch2\u003eInflammatory markers\u003c/h2\u003e \u003cp\u003eIn our study, commonly utilized inflammatory markers, including the neutrophil-to-lymphocyte ratio (NLR) and C-reactive protein (CRP) \u003csup\u003e\u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e, exhibited no significant differences between patients with and without thrombocytopenia. While these indices are commonly employed as indicators of systemic inflammation in critically ill patients, they may exhibit reduced sensitivity to the complex mechanisms driving platelet consumption and destruction in the ICU environment. Likewise, the AST/ALT ratio was moderately elevated in patients with TP. High AST/ALT ratios in very sick patients are often seen as signs of systemic stress, low blood flow, or extrahepatic AST release, not just liver cell damage\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e. These results indicate that standard inflammatory indices may inadequately reflect the intricate inflammatory and coagulopathic mechanisms linked to thrombocytopenia in critically ill patients.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec19\" class=\"Section2\"\u003e \u003ch2\u003eDuration of thrombocytopenia\u003c/h2\u003e \u003cp\u003eOur findings regarding the prognostic significance of TP duration are particularly valuable: an increase in mortality was observed in cases of TP lasting\u0026thinsp;\u0026ge;\u0026thinsp;3 days. This is consistent with recent multicohort analyses supporting the concept of \u0026ldquo;persistent/chronic sepsis-associated thrombocytopenia\u0026rdquo;; it has been shown that the risk of poor outcomes increases as the duration prolongs\u003csup\u003e\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e\u003c/sup\u003e. Clinically, this result suggests that in ICU monitoring, the trend and rate of recovery may be more meaningful than a single platelet count (PC). On the other hand, the fact that no significant difference in mortality was observed between the presence of TP at admission ICU and its development during the course of treatment emphasizes that \u0026ldquo;developing TP is at least as important as TP at admission\u0026rdquo; in clinical practice. This finding supports the interpretation that TP may be a dynamic marker that emerges as systemic inflammation and organ failure worsen during the course of ICU.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec20\" class=\"Section2\"\u003e \u003ch2\u003ePlatelet thresholds and relative thrombocytopenia\u003c/h2\u003e \u003cp\u003eThe definition of thrombocytopenia varies considerably across the literature, and no universally accepted diagnostic threshold exists. While most studies define TP using an absolute platelet count\u0026thinsp;\u0026lt;\u0026thinsp;150\u0026times;10⁹/L, other thresholds and relative platelet decline criteria have also been proposed. When absolute PCs are used, a wide range of threshold values has been reported, including 200\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, 150\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L, 80\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L and 60\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. Similarly, studies based on platelet decline have applied reductions of \u0026gt;\u0026thinsp;30% or \u0026gt;\u0026thinsp;50% as diagnostic thresholds\u003csup\u003e\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e. Nevertheless, in contemporary clinical practice and in the majority of published studies, TP is most commonly defined as an absolute PC\u0026thinsp;\u0026lt;\u0026thinsp;150\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L\u003csup\u003e11\u003c/sup\u003e. In our study, the modest discriminatory performance of PC in predicting ICU mortality (AUC\u0026thinsp;=\u0026thinsp;0.58) indicates that PC alone is a weak prognostic marker. Although it is a weak independent predictor in organ failure modeling (due to the heavy dominance of the need for mechanical ventilation in model calibration), we also found that it is weakly associated with mortality when evaluated with DIC These findings indicate that TP may function both as a marker of critical illness severity and as a component of the complex inflammatory and coagulative cascade underlying mortality in ICU patients. Specifically, the higher optimal threshold value (\u0026lt;\u0026thinsp;200\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L) determined using the Youden index suggests that clinically meaningful platelet decline may occur earlier and with relatively smaller decreases than those captured by the traditional\u0026thinsp;\u0026lt;\u0026thinsp;150\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L threshold. Although PC\u0026thinsp;\u0026lt;\u0026thinsp;200\u0026times;10\u003csup\u003e9\u003c/sup\u003e/L does not meet the official definition of TP, it has been defined as \u0026ldquo;Relative Thrombocytopenia\u0026rdquo; \u003csup\u003e30\u003c/sup\u003e to facilitate the early diagnosis of high-risk patients. Although RTP is not associated with mortality (in our study, it was associated with ICU mortality), we propose the definition of \u0026ldquo;Subthreshold TP\u0026rdquo; for ICU patients as an early indicator of disease severity and recommend further studies. However, these findings may be influenced by center-specific characteristics, patient case diversity, and timing of measurement, and therefore require external validation.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec21\" class=\"Section2\"\u003e \u003ch2\u003eSteroid and antibiotic therapy\u003c/h2\u003e \u003cp\u003eCorticosteroid use was more frequent among patients with TP. This finding likely reflects greater disease severity rather than a direct effect of corticosteroids on PCs. In critically ill patients, corticosteroids are commonly administered in the context of septic shock, refractory hypotension, or severe systemic inflammation\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e clinical scenarios that are themselves strongly associated with TP. Similarly, antibiotic use was highly prevalent in both groups and did not differ significantly between patients with and without TP. While certain antibiotics have been implicated in drug-induced thrombocytopenia, such effects are relatively uncommon and often difficult to distinguish from sepsis-related platelet consumption in critically ill patients\u003csup\u003e\u003cspan citationid=\"CR31\" class=\"CitationRef\"\u003e31\u003c/span\u003e\u003c/sup\u003e. In this context, the lack of a significant association between antibiotic therapy and TP supports the interpretation that TP in our cohort predominantly reflects underlying disease processes rather than antibiotic exposure per se.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec22\" class=\"Section2\"\u003e \u003ch2\u003eTransfusion and complications\u003c/h2\u003e \u003cp\u003eIn terms of transfusion and complications, the higher use of blood and blood products in the TP group Patients with TP required significantly more blood and blood product transfusions. However, the absence of a significant difference in bleeding complications between groups may be related to our patient selection criteria and the restrictive transfusion strategies used in our centre. Current intensive care guidelines support a shift from \u0026ldquo;routine practices\u0026rdquo; to evidence-based, more restrictive strategies based on clinical context in transfusion decisions for critically ill patients without bleeding\u003csup\u003e\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e\u003c/sup\u003e. We believe that the real-world data from your study provides valuable insight into how TP affects transfusion decisions and invasive procedure planning in the clinical setting.\u003c/p\u003e \u003cdiv id=\"Sec23\" class=\"Section3\"\u003e \u003ch2\u003eStrengths and Limitations of the Study\u003c/h2\u003e \u003cp\u003eSeveral limitations of this study should be acknowledged. Its single-center design may limit the generalizability of the findings and the exclusion of certain patient groups, such as those with end stage cirrhosis or uncontrolled major bleeding, may have influenced the observed associations. As a single-center observational study, residual confounding and selection bias cannot be completely excluded, despite the prospective design and systematic data collection. in septic patients, sepsis was accepted as the primary etiology of TP and platelet consumption and increased destruction were simultaneously considered as underlying mechanisms. While this approach reflects routine clinical practice in the ICU, it may have led to overlapping etiological and mechanistic classifications and limited causal interpretation regarding specific pathways. Nevertheless, a comprehensive assessment of clinical and laboratory variables, along with detailed subgroup analyses based on thrombocytopenia severity, persistence, and timing, strongly emphasizes the clinical significance of TP and RTP (Subthreshold TP) in medical intensive care settings.\u003c/p\u003e \u003c/div\u003e \u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eThrombocytopenia is prevalent among critically ill patients and is strongly correlated with disease severity, organ dysfunction, and mortality. Our findings highlight that not only the presence but also the severity and persistence of thrombocytopenia carry important prognostic information. Additionally, a decrease in platelets beyond the standard thrombocytopenia threshold may indicate an early sign of clinical worsening. These observations support the interpretation of thrombocytopenia as a dynamic biomarker of critical illness rather than merely a laboratory abnormality. Future multicentre studies are needed to validate the concept of subthreshold thrombocytopenia and to clarify its potential role in early risk stratification in ICU patients.\u003c/p\u003e"},{"header":"Abbreviations","content":"\u003cp\u003eALI \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Acute Liver Injury\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eALF\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Acute Liver Failure\u003c/p\u003e\n\u003cp\u003eAKI\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Acute Kidney Injury\u003c/p\u003e\n\u003cp\u003eAPACHE-II\u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Acute Physiology and Chronic Health Evaluation II\u003c/p\u003e\n\u003cp\u003eAT \u0026nbsp;\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Any Thrombocytopenia\u003c/p\u003e\n\u003cp\u003eCBC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Complete Blood Count\u003c/p\u003e\n\u003cp\u003eCVC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Central Venous Catheter\u003c/p\u003e\n\u003cp\u003eDIC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Disseminated Intravascular Coagulation\u003c/p\u003e\n\u003cp\u003eFFP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Fresh Frozen Plasma\u003c/p\u003e\n\u003cp\u003eGCS\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Glaskow Coma Scale\u003c/p\u003e\n\u003cp\u003eHIT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Heparin-induced thrombocytopenia\u003c/p\u003e\n\u003cp\u003eICU\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Intensive Care Unit\u003c/p\u003e\n\u003cp\u003eICU-TP\u0026nbsp;ICU Acquired Thrombocytopenia\u003c/p\u003e\n\u003cp\u003eIT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Initial Thrombocytopenia\u003c/p\u003e\n\u003cp\u003eLMWH\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Low Molecular Weight Heparin\u003c/p\u003e\n\u003cp\u003eMV\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Mechanical Ventilation\u003c/p\u003e\n\u003cp\u003eNT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Never Thrombocytopenia\u003c/p\u003e\n\u003cp\u003ePC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Platelet Counts (PC)\u003c/p\u003e\n\u003cp\u003eRBC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Red Blood Cell\u003c/p\u003e\n\u003cp\u003eRRT\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Renal Replacement Therapy;\u003c/p\u003e\n\u003cp\u003eRTP Relative Thrombocytopenia\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSTP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Subthreshold thrombocytopenia\u003c/p\u003e\n\u003cp\u003eTP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;Thrombocytopenia\u003c/p\u003e\n\u003cp\u003eVP\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;Vasopressor\u003c/p\u003e\n\u003cp\u003eWBC\u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;White Blood Cell\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe study is based on the ICU cohort of the Kayseri City Hospital which consists: A prospective cohort starting in September 2023 and August 2024. The Ethics Committee approval for the ICU cohort is dated July 25, 2023, and numbered 877. \u0026nbsp;It was conducted in accordance with the Declaration of Helsinki. All patients provided written informed consent\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability statement:\u003c/strong\u003e\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eDeclaration of competing interest\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions (CRediT Statement)\u003c/strong\u003e\u003cstrong\u003e:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKamil Deveci\u003c/strong\u003e: Writing\u0026ndash;review\u0026amp;editing, Writing\u0026ndash;original draft, Data curation, \u0026nbsp;Project administration, Resources, Methodology, Investigation, Formal analysis, Data curation, Conceptualization, Supervision. \u003cstrong\u003eMaruf Boran:\u003c/strong\u003e Writing\u0026ndash;review\u0026amp;editing, Supervision, Methodology, Formal analysis, Data curation, Conceptualization. \u003cstrong\u003eK\u0026uuml;bra E. Bahar:\u003c/strong\u003e Writing\u0026ndash;review\u0026amp;editing, Supervision, Resources, Methodology, Formal analysis, Data curation, Conceptualization. \u003cstrong\u003eFatma Sarıdağ:\u003c/strong\u003e Writing\u0026ndash;review\u0026amp;editing, Supervision, Resources, Methodology, Formal analysis, Data curation, Conceptualization\u003cstrong\u003e\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements:\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eDuring the preparation of this work the authors used ChatGPT (OpenAI) and NotebookLM in order to English language editing and stylistic improvement. After using this tool, the authors reviewed and edited the content as needed and takes full responsibility for the content of the published article.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eP\u0026egrave;ne F, Russell L, Aubron C. Thrombocytopenia in the intensive care unit: diagnosis and management. Ann Intensive Care. 2025;15(1):25. Published 2025 Feb 22. doi:10.1186/s13613-025-01447-x\u003c/li\u003e\n\u003cli\u003eJonsson AB, Ryg\u0026aring;rd SL, Hildebrandt T, Perner A, M\u0026oslash;ller MH, Russell L. Thrombocytopenia in intensive care unit patients: A scoping review. Acta Anaesthesiol Scand. 2021;65(1):2-14. doi:10.1111/aas.13699\u003c/li\u003e\n\u003cli\u003eAnthon CT, P\u0026egrave;ne F, Perner A, et al. Platelet transfusions in adult ICU patients with thrombocytopenia: A sub-study of the PLOT-ICU inception cohort study. Acta Anaesthesiol Scand. 2024;68(8):1018-1030. doi:10.1111/aas.14467\u003c/li\u003e\n\u003cli\u003eOstadi Z, Shadvar K, Sanaie S, Mahmoodpoor A, Saghaleini SH. Thrombocytopenia in the intensive care unit. Pak J Med Sci. (2019) 35:282\u0026ndash;7. doi: 10.12669/pjms.35.1.19\u003c/li\u003e\n\u003cli\u003eMenard CE, Kumar A, Houston DS, et al. Evolution and Impact of Thrombocytopenia in Septic Shock: A Retrospective Cohort Study. 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Thrombocytopenia in the critically ill: Prevalence, incidence, risk factors, and clinical outcomes. Canadian 29 Journal of Anesthesia 2013; 60: 641-51\u003c/li\u003e\n\u003cli\u003eBen Hamida C, Lauzet JY, Rezaiguia-Delclaux S, Duvoux C, Cherqui D, Duvaldestin P, Stephan F. Effect of severe thrombocytopenia on patient outcome after 3 liver transplantation. Intensive Care Med 2003; 29: 756-62\u003c/li\u003e\n\u003cli\u003eThachil J, Warkentin TE. How do we approach thrombocytopenia in critically ill patients?. Br J Haematol. 2017;177(1):27-38. doi:10.1111/bjh.14482\u003c/li\u003e\n\u003cli\u003eSinger M, Deutschman CS, Seymour CW, et al. The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). JAMA. 2016;315(8):801-810. doi:10.1001/jama.2016.0287\u003c/li\u003e\n\u003cli\u003eKumar A, Mhaskar R, Grossman BJ, Kaufman RM, Tobian AAR, Kleinman S, Gernsheimer T, Tinmouth AT, Djulbegovic B, Panel APTG. 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Life (Basel). 2025;15(2):274. Published 2025 Feb 11. doi:10.3390/life15020274\u003c/li\u003e\n\u003cli\u003eLiang P, Yu F. Value of CRP, PCT, and NLR in Prediction of Severity and Prognosis of Patients With Bloodstream Infections and Sepsis. Front Surg. 2022;9:857218. Published 2022 Mar 7. doi:10.3389/fsurg.2022.857218\u003c/li\u003e\n\u003cli\u003eWang L, Jin P, Hui Y, et al. A non-linear association between AST/ALT ratio and 28-day mortality in critically ill elderly: evidence from a multicenter study. Sci Rep. 2025;15(1):25831. Published 2025 Jul 16. doi:10.1038/s41598-025-11220-6\u003c/li\u003e\n\u003cli\u003eKutcher ME, Cripps MW, McCreery RC, et al. Criteria for empiric treatment of hyperfibrinolysis after trauma. J Trauma Acute Care Surg. 2012;73(1):87-93. doi:10.1097/TA.0b013e3182598c70\u003c/li\u003e\n\u003cli\u003ePriziola JL, Smythe MA, Dager WE. Drug-induced thrombocytopenia in critically ill patients. Crit Care Med. 2010;38(6 Suppl):S145-S154. doi:10.1097/CCM.0b013e3181de0b88\u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTables 1 to 8 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Persistent Thrombocytopenia, Relative Thrombocytopenia, Platelet Dynamics, Subthreshold Thrombocytopenia, Mortality","lastPublishedDoi":"10.21203/rs.3.rs-9178594/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-9178594/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eThrombocytopenia (TP) is common in intensive care unit (ICU) patients and has been associated with increased morbidity and mortality. However, the prognostic importance of platelet dynamics remains incompletely understood. We aimed to evaluate the prognostic impact of platelet dynamics and subthreshold/relative thrombocytopenia (\u0026lt;\u0026thinsp;200 \u0026times;10⁹/L) in ICU patients.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eIn this prospective observational cohort study, 280 adult patients admitted to the medical ICU were followed. TP was defined as PC\u0026thinsp;\u0026lt;\u0026thinsp;150 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L and Subthreshold thrombocytopenia (STP) as PC\u0026thinsp;\u0026lt;\u0026thinsp;200 \u0026times;10\u003csup\u003e9\u003c/sup\u003e/L. Patients were evaluated according to the presence, severity, duration (\u0026ge;\u0026thinsp;3 days vs\u0026thinsp;\u0026lt;\u0026thinsp;3 days), and timing of TP (initial vs ICU-acquired). Clinical outcomes were analyzed. Multivariable logistic regression models was performed to determine independent predictors of ICU mortality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eTP occurred in 42.1% of patients and was strongly associated with increased ICU, hospital, 28-day, and 90-day mortality (all p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). Mortality increased progressively with greater TP severity. Persistent TP (\u0026ge;\u0026thinsp;3 days) was independently associated with ICU mortality (aOR 2.75, 95% CI 1.50\u0026ndash;5.02). Platelet count alone demonstrated limited discriminatory ability for predicting ICU mortality (AUC 0.58). Notably, a platelet threshold around 200 \u0026times;10⁹/L provided a more balanced sensitivity and specificity compared with the conventional 150 \u0026times;10⁹/L cut-off. Patients with STP showed greater disease severity and increased ICU mortality and need for organ support.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eBeyond its presence alone, the severity and persistence of TP provide important prognostic information in critically ill patients. Our findings suggest that STP may represent an early marker of clinical deterioration, highlighting the potential role of STP as a dynamic biomarker for early risk stratification in ICU populations\u003c/p\u003e","manuscriptTitle":"The Prognostic Impact of the Platelet Dynamics and Subthreshold Thrombocytopenia in Intensive Care Patients: A Prospective Cohort Study","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2026-04-19 12:26:25","doi":"10.21203/rs.3.rs-9178594/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"reviewerAgreed","content":"101828446085665197478186258719572374507","date":"2026-05-18T04:05:41+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"304749950780318089441127698557820851978","date":"2026-05-18T03:33:19+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"85705354025587451889694384870334075526","date":"2026-05-12T08:46:03+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"103074851495728761398462304810291158017","date":"2026-05-11T08:26:55+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2026-04-26T00:48:56+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"96843790521298819889839192692720293290","date":"2026-04-25T13:34:33+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2026-04-09T23:30:06+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2026-04-09T23:26:41+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2026-03-26T11:31:46+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2026-03-24T09:04:24+00:00","index":"","fulltext":""},{"type":"submitted","content":"Scientific Reports","date":"2026-03-24T08:58:33+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"scientific-reports","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"scirep","sideBox":"Learn more about [Scientific Reports](http://www.nature.com/srep/)","snPcode":"","submissionUrl":"","title":"Scientific Reports","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"stoa","reportingPortfolio":"Scientific Reports","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fa5253a9-7a79-4243-a79a-e6b66495c3bc","owner":[],"postedDate":"April 19th, 2026","published":true,"recentEditorialEvents":[{"type":"reviewerAgreed","content":"101828446085665197478186258719572374507","date":"2026-05-18T04:05:41+00:00","index":479,"fulltext":""},{"type":"reviewerAgreed","content":"304749950780318089441127698557820851978","date":"2026-05-18T03:33:19+00:00","index":478,"fulltext":""},{"type":"reviewerAgreed","content":"85705354025587451889694384870334075526","date":"2026-05-12T08:46:03+00:00","index":457,"fulltext":""},{"type":"reviewerAgreed","content":"103074851495728761398462304810291158017","date":"2026-05-11T08:26:55+00:00","index":456,"fulltext":""}],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":66351910,"name":"Health sciences/Biomarkers"},{"id":66351911,"name":"Health sciences/Diseases"},{"id":66351912,"name":"Health sciences/Medical research"},{"id":66351913,"name":"Health sciences/Risk factors"}],"tags":[],"updatedAt":"2026-04-19T12:26:25+00:00","versionOfRecord":[],"versionCreatedAt":"2026-04-19 12:26:25","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-9178594","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-9178594","identity":"rs-9178594","version":["v1"]},"buildId":"XKTyCvWXoU3ODBz1xrDgd","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}