Prognostic Significance of Thrombocytopenia and Mean Platelet Volume in COPD Patients with Acute Exacerbations in ICU Settings

Introduction

Chronic obstructive pulmonary disease (COPD) is one of the leading causes of death worldwide, and the mortality rate varies according to the severity of the disease and patients [1,2]. Although the prevalence of COPD varies between 5% and 17%, it is a particularly common comorbid condition in the İntensive Care Unit (ICU) [3]. Smoking is an important risk factor for this disease, and other factors such as exposure to indoor and outdoor air pollution, occupational hazards, and infections are also risk factors [3]. According to the GOLD criteria, COPD is diagnosed in the presence of persistent airflow limitation on pulmonary function testing, “appropriate symptoms” including shortness of breath, chronic cough, expectoration, or wheezing, and “significant exposure to noxious stimuli” such as smoking history or other environmental exposures [4]. When complications of AECOPD such as pulmonary hypertension, carbon dioxide retention (decreased alertness), hemodynamic instability, or arrhythmia develop, patients must be hospitalized [5]. The severity and frequency of exacerbations are strongly associated with mortality [6].

In terms of both cost and extended hospitalization, it is extremely important to detect patients who may have a poor prognosis and mortality estimate early and to make appropriate therapeutic interventions. Using markers that do not require additional costs, such as complete blood count, which can be looked at quickly in all centers in the prediction of mortality and prognosis, has advantages in terms of time and cost [7].

Platelets are cells of critical importance in hemostasis and thrombosis. Megakaryocytes in the bone marrow produce platelets [8]. Interestingly, several studies have shown large numbers of megakaryocytes in the lungs, suggesting that the lungs may be a specific organ for platelet biogenesis [8]. In addition to their established roles in hemostasis and thrombosis, platelets are known to exert important modulatory effects on inflammatory and immune-mediated pathways. This further supports their role in the pathogenesis and progression of COPD, a disease characterized by airway inflammation, excessive mucus production, progressive destruction of the lung parenchyma with loss of elasticity, and abnormal remodeling of the pulmonary vasculature. In addition to platelet count, platelet markers such as MPV have also been used for clinical and research purposes in respiratory diseases [9]. Platelet activation and increased coagulation in patients with COPD, along with oxidative stress, can exacerbate atherosclerosis [10]. This situation is also related to significantly increased platelet counts in patients with COPD [11]. In general, it has been shown that the platelet count in COPD patients is higher than in the general population [12]. On the contrary, it has been shown that there is a relationship between thrombocytopenia and high mortality during acute exacerbation of COPD (AECOPD), and that there is a significant increase in the length of stay in the ICU and hospital, and the need for mechanical ventilation with thrombocytopenia [13]. When looking at the relationship between MPV and COPD, some studies have shown that MPV values are higher in COPD patients, while other studies have reported that MPV values are lower. However, it has been observed that the MPV value increases during the acute exacerbation period of COPD and is an important tool in evaluating the inflammatory response [14].

In ICU patients, anticoagulant use and infection also have negative effects on platelet count and function [15]. Platelets play a central role in sepsis as they affect hemostasis and immune response. Thrombocytopenia may also result from peripheral overconsumption (eg, activation of platelet membrane receptors, hemophagocytosis, or disseminated intravascular coagulation activation) [16].

Therefore, this retrospective study of 472 patients admitted to the ICU with an AECOPD aimed to evaluate the association of thrombocytopenia and MPV with prognosis and mortality.

Material and Methods

ETHICS STATEMENT, STUDY DESIGN, AND RESEARCH PARTICIPANTS:

After the study protocol was approved by our Institutional Ethics Committee (Ethical Decision No: 2021-KAEK-15/2643 dated 08.02.2023), patients’ data were retrospectively examined. The study was conducted according to the Declaration of Helsinki. The institutional review board waived the requirement for written informed consent due to the retrospective nature of the study.

The data of 686 patients hospitalized with the diagnosis of AECOPD in the tertiary adult intensive care unit of Ankara Atatürk Sanatorium Training and Research Hospital between 1 April 2018 and 11 May 2021 were examined. When those with active bleeding, with hematological comorbidities, using antithrombotic drugs, with malignancies, and receiving chemotherapy and/or radiotherapy were excluded, after which 472 patients were included in the study.

INCLUSION AND EXCLUSION CRITERIA:

We enrolled patients over the age of 18 years, who were previously diagnosed with COPD according to the Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, were admitted to the ICU due to acute exacerbation, and stayed in the ICU for more than 24 h.

According to GOLD criteria; It is necessary to suspect COPD in case of symptoms such as decrease in activity, shortness of breath, chronic cough, sputum production or wheezing, and the presence of risk factors such as smoking history, environmental exposure, and/or family history of COPD. In cases of suspected COPD, spirometry is required to confirm the diagnosis of COPD. A ratio of postbronchodilator forced expiratory volume in 1 second (FEV1) to forced vital capacity (FVC) <0.70 confirms the presence of persistent or fixed airflow restriction [17].

According to GOLD, AECOPD is defined as an event associated with a worsening of symptoms due to infection, pollution, or another noxious agent to the respiratory tract, an increase in tachypnea and/or tachycardia in <14 days, and, often, an increase in local and systemic inflammation. Comorbidities that frequently occur in patients (eg, acute myocardial infarction, congestive heart failure, cardiac arrhythmias, and pulmonary embolism) can mimic AECOPD symptoms [17].

In our study, the diagnosis of AECOPD was made by pulmonologists according to the GOLD criteria, taking into account the patients’ comorbidities. We excluded patients under 18 years of age, those with active bleeding or a hematological comorbidity, those who had used antithrombotic drugs, those with malignancies, and those receiving chemotherapy and/or radiotherapy.

DATA COLLECTION METHODS:

Data were recorded retrospectively in an Excel file by the corresponding author through computer database and patient file scanning. The blood values of the patients during their admission to the ICU were examined.

In this study, which investigated the effect of thrombocytopenia on prognosis and mortality in AECOPD patients, the platelet count for thrombocytopenia was considered to be 100×10⁹/L and below. Above 100×10⁹/L was classified as normal platelet value. The data from thrombocytopenic patients with a platelet count of 100×10⁹/L and those with a platelet count above 100×10⁹/L were compared. We accepted values of 100×10⁹/L and below in our study because the World Health Organization defines thrombocytopenia as a platelet count below 100×10⁹/L. Since the MPV value reference range of our hospital is 7–11, MPV classification was made by dividing it into 3 groups: values above 11, values 7–11, and values below 7. MPV values below 7 are classified as low MPV, values between 7 and 11, including 7 and 11, are classified as normal MPV values, and values above 11 are classified as high MPV.

In our study, complete blood count measurements were measured with the Mindray BC 6800 (Shenzhen Mindray Bio-medical Electronics Co., Ltd. China) automatic complete blood count device. With the impetance method platelets are assessed by counting the platelets passing directly through the aperture and results are expressed as 10⁹/L. Mean platelet volume (MPV, fL) measurement was simultaneously calculated based on the platelet histogram.

Patient age, sex, body mass index (BMI), comorbidities, Acute Physiology and Chronic Health Evaluation-2 (APACHE-II) score, Sequential Organ Failure Assessment (SOFA) score during ICU admission, Charlson Comorbidity Index Score (CCIS), complete blood count, C-reactive protein (CRP) and procalcitonin values, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin values during ICU admission, duration of mechanical ventilation during ICU stay, presence of type 1 and type 2 respiratory failure, need for inotropic agent support during ICU follow-up, ICU and hospital stay durations, and 28-day mortalities were recorded.

STATISTICAL ANALYSIS:

Data analyses were performed by using SPSS for Windows, version 22.0 (SPSS, Inc., Chicago, IL, United States). Normal distribution of continuous variables was determined by the Kolmogorov-Smirnov test. The Levene test was used for evaluation of homogeneity of variances. Unless specified otherwise, continuous data are described as mean±SD and median (interquartile range). Categorical data are described as number of cases (%). Statistical analysis differences in non-normally distributed variables between 2 independent groups were compared using the Mann-Whitney U test. Categorical variables were compared using Pearson’s chi-square test or Fisher’s exact test. The Conover-Inman test was performed for binary comparisons among the MPV groups, and the P value was set at 0.05. Univariate and multivariate logistic regression analyses were performed to assess the association between mortality and the risk factors findings. As a result of univariate logistic regression analysis, values with a P value below 0.25 were included in the multivariate logistic regression analysis. Enter method was used in multivariate logistic regression analysis. P values <0.05 were regarded as significant in all statistical analyses.

Results

COMPARISON OF COPD PATIENTS ACCORDING TO PLATELET VALUES:

In this retrospective study, 472 patients admitted to the adult tertiary general ICU with the diagnosis of AECOPD were evaluated and divided into 2 groups according to platelet values. Those with a platelet count ≤100×10⁹/L were classified into the thrombocytopenia group, and those with platelet counts >100×10⁹/L were classified as having normal platelet values.

When patients with thrombocytopenia were compared to those with normal platelet values, it was observed that the in-hospital albumin, white blood cell count, and lymphocyte count were significantly lower, while the mortality rate, APACHE-II score, CCIS, duration of mechanical ventilation, and SOFA scores were significantly higher in patients with thrombocytopenia (Table 1).

MORTALITY ASSESSMENT:

When patients were analyzed according to 1-month mortality values, it was found that the age, need for inotropic support, APACHE-II, CCIS, SOFA scores, neutrophil, ALT, AST, leukocyte, CRP, procalcitonin values, and duration of mechanical ventilation were significantly higher in patients who died than in those who were discharged. Additionally, hospital stay duration, and albumin, lymphocyte (%), and platelet values were significantly lower in patients who died than in those were discharged (Table 2).

COMPARISON OF COPD PATIENTS ACCORDING TO MPV VALUES:

Patients were divided into 3 groups according to MPV values: low MPV (MPV <7 fl), normal MPV (MPV=7–11 fl) and high MPV (>7 fl). Accordingly, there were statistically significant differences between the groups in terms of BMI, mortality, APACHE-II score, CCIS, platelet count, and SOFA score (P<.05). Post hoc test results were applied to determine which of these differences originated from which 2 groups, showing that the mortality rate was highest in patients with MPV >11 ft and lowest in patients with MPV <7 ft, with statistically significant differences between all groups. When comparing patients with an MPV <7 ft to those with an MPV of 7–11 ft, it was found that the BMI values of patients with an MPV <7 ft were significantly higher, while their CCIS scores were significantly lower. The APACHE-II scores of patients with MPV >11 ft were significantly higher than those of patients with MPV 7–11 ft. When comparing patients with an MPV >11 ft to those with an MPV <7 ft, it was found that patients with an MPV> 11 ft had significantly lower platelet values and higher SOFA scores (Table 3).

LOGISTIC REGRESSION ANALYSIS EVALUATIONS:

Univariate logistic regression analysis was performed to identify factors affecting mortality in patients. Variables with a P value <0.05 have a high probability of predicting mortality according to the univariate analysis. Accordingly, it was observed that older age, thrombocytopenia, APACHE-II score, ICU stay duration, MV duration, leukocyte count, MPV, CRP, procalcitonin, SOFA score, shorter hospital stay, and albumin value predicted mortality. Variables found to be P<0.25 in univariable logistic regression analysis were included in the multivariable logistic regression analysis. The entry method was used in the multivariable logistic regression analysis. According to the result of multivariable logistic regression analysis, an increase in APACHE-II score (OR (95% CI): 1.076 (1.009–1.147)), ICU stay duration (OR (95% CI): 0.898 (0.828–0.973)), MV duration (OR (95% CI): 1.177 (1.095–1.265)), leukocyte value (OR (95% CI): 1.147 (1.083–1.214)), SOFA score (OR (95% CI): 1.993 (1.506–2.638)), and a decrease in hospital stay duration (OR (95% CI): 0.971 (0.945–0.998)) and albumin value (OR (95% CI): 0.172 (0.088–0.337)) were found to predict mortality (Table 4).

Discussion

In this study, which included 472 patients admitted to the ICU due to AECOPD, the relationship between changes in thrombocytopenia and MPV values and prognosis and mortality was investigated. We found that older age, high APACHE-II and SOFA scores, thrombocytopenia, MPV value >11, long ICU stay, prolonged duration of mechanical ventilation, hypoalbuminemia, leukocytosis, CRP, and procalcitonin levels were associated with mortality.

In a study examining 200 patients with AECOPD, thrombocytopenia was observed in 27.5% of patients [13], while in our study, the rate of thrombocytopenia was 5.5%. The reason for this rate being lower than that of other sources is the difference in platelet threshold values accepted for thrombocytopenia. In other studies, values below 150×109/L were considered thrombocytopenia, while in our study values of 100×109/L and below were accepted as thrombocytopenia because the World Health Organization defines thrombocytopenia as a platelet count below 100×109/L [18].

In a study showing mortality in COPD patients, the mortality rate in the thrombocytopenia group was 86.4%, and a significant difference was observed when compared to those who did not develop thrombocytopenia. They also emphasized that a 10% decrease in platelet count could be considered an independent predictor of ICU mortality [19]. In another study, statistically significant thrombocytopenia was observed in approximately 47.1% of patients who died in the ICU [20]. The mortality rate due to thrombocytopenia in ICU patients varies in the literature. Our study also shows that the mortality rate is high (61.5%) when thrombocytopenia occurs in AECOPD patients.

In a study comparing 11 941 patients with pulmonary infection to those with other infectious diseases, low partial arterial oxygen pressure (PaO2) and COPD were found to be significant risk factors for thrombocytopenia. To investigate the mechanism of thrombocytopenia, a hypoxic mouse model was created, and it was observed that there were fewer platelets in hypoxic mice. It is speculated that low PaO2 can induce thrombocytopenia by disrupting platelet production in the lungs [8]. The ongoing presence of hypoxia and hypercarbia are the main reasons for the prolongation of mechanical ventilation duration. This supports our finding that prolonged mechanical ventilation duration is a risk factor for thrombocytopenia.

High APACHE-II and SOFA scores have been found to be risk factors for thrombocytopenia associated with early septic shock [21]. When calculating the APACHE-II score, PaO2 is also assessed; therefore, the APACHE-II score was higher in patients with hypoxia. The higher rate of thrombocytopenia in patients with a high APACHE-II score in our study could be due to hypoxia-increasing thrombocytopenia. The drop in platelet value, which is considered when calculating the SOFA score used in the diagnosis and prognosis of sepsis, causes the SOFA score to rise. Sepsis is one of the leading causes of thrombocytopenia in thrombocytopenic patients [22]. In patients with thrombocytopenic COPD, bacterial infections and sepsis have been associated with poor prognosis [13]. A study has shown that thrombocytopenia in the early stages in patients with septic shock is associated with higher mortality, and that there is an increase in mortality with the severity of thrombocytopenia [23]. In our study, we also found a significant relationship between thrombocytopenia and infection and sepsis, such as high SOFA scores, leukocytosis, and increased CRP and procalcitonin levels in AECOPD patients.

MPV and MPV/platelet ratio should be considered as tools primarily guiding the treatment of sepsis in low-resource settings, as they are low-cost determinants of clinical severity and mortality in sepsis [24]. A high MPV level is an independent risk factor for increased in-hospital mortality in patients with severe pneumonia [25]. Worsening hypoxemia increases MPV and platelet activity, volume, and aggregation [26,27]. In a study of patients with COPD, the MPV values in the stable period were higher than those in the control group [19]. In patients with acute stroke, thrombocytopenia and a high MPV are associated with mortality [29]. In our study, thrombocytopenia and mortality rates were higher in patients with high MPV values. We believe that this could be secondary to the hypoxia that occurs during AECOPD.

The platelet-albumin ratio is a new indicator that reliably reflects immune system status, systemic inflammation, and immune nutrition status in various diseases [30]. In severe COPD patients with acute exacerbations, serum albumin measured within the first 24 h after hospital admission is predictive of in-hospital mortality [31]. The presence of hypoalbuminemia and thrombocytopenia within 24 h of hospitalization has been shown to be associated with poor prognosis and high mortality [32]. In the present study, hypoalbuminemia was a risk factor for mortality and thrombocytopenia.

Our study has some limitations. The inference made between the groups was limited because there were few patients in the thrombocytopenia group. Furthermore, the interaction between platelet formation in the lungs and low PaO2 could not be fully clarified. Although patients with diseases and treatments affecting platelet levels were excluded from the study, platelet and MPV levels may have been affected due to unregistered situations. The findings of this study need to be confirmed by large-scale prospective studies.

Conclusions

In this study, mortality in AECOPD patients was found to be higher in those with a platelet value <100×109/L than in those with a platelet value ≥100×109/L and in those with an MPV value over 11 fl compared to those with an MPV value ≤11 fl. We found that thrombocytopenia, high MPV, high APACHE-II and SOFA scores, ICU and hospital LOS, duration of mechanical ventilation, leukocytosis, and hypoalbuminemia predicted mortality. Since this situation may worsen due to infection-sepsis, hypoalbuminemia, and hypoxia, we think that early infection control, albumin support and preventing hypoxia will contribute significantly to reducing thrombocytopenia and mortality. Preventing thrombocytopenia, which leads to longer duration of stay and mechanical ventilation in the ICU, will enable more effective ICU use.