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Clinical Aspects

Clinical Significance of Tissue Factor and CD13 Double-Positive Microparticles in Sirs Patients with Trauma and Severe Sepsis

Matsumoto, Hisatake; Yamakawa, Kazuma; Ogura, Hiroshi; Koh, Taichin; Matsumoto, Naoya; Shimazu, Takeshi

Author Information
doi: 10.1097/SHK.0000000000000768

Abstract

INTRODUCTION

The pathogenesis of systemic inflammatory response syndrome (SIRS) results from the increased release of pro-inflammatory cytokines and inflammatory mediators during an immunological response. Exacerbation of systemic inflammation often progresses to multiple organ failure (MOF) leading to a lethal outcome (1). Thus, SIRS is an important condition to address in critically ill patients. However, the pathogenesis of SIRS, such as that following trauma and sepsis, has not been thoroughly clarified.

Microparticles (MPs) are small membrane-bound vesicles that are released from various cells upon activation such as monocytes, platelets, erythrocytes, neutrophils, and endothelial cells. MPs play multiple roles in pathology and are important for maintaining homeostasis (2). MPs have been recognized as inflammatory mediators in various inflammatory diseases (3). We previously reported that endothelial and platelet MPs increase and could play an important role as inflammatory mediators in the pathogenesis of SIRS resulting from trauma or sepsis (4, 5). Immune cells such as monocytes have been shown to play important roles as immunological response cells in the development of SIRS (6, 7). The activated monocytes synthesize and express almost all of the tissue factor (TF) in the blood cells (8, 9), which manifests not only as a hypercoagulable but also as an inflammatory state (10). Expression of cell-specific surface antigens such as TF on MPs has recently become a focus of current research. Several reports have shown that TF on MPs has its own specific bioactivity, and TF-positive MPs are associated with both inflammation and coagulation (11–13).

CD13 is a cell-surface ectoenzyme expressed on several granulocytes but mainly monocytes (14, 15). TF, which is synthesized and expressed almost only on activated monocytes (13) and CD13 double-positive MPs (TF+/CD13+MPs), is predominantly produced from the activated monocytes. The objective of this study was to evaluate the practical importance of TF+/CD13+MPs in the pathogenesis of SIRS early after trauma or sepsis.

PATIENTS AND METHODS

Patients

This prospective study was conducted at the Department of Traumatology and Acute Critical Medicine, Osaka University Graduate School of Medicine, from November 2012 to February 2015. Trauma patients with SIRS suffering from blunt or penetrating injury and patients with severe sepsis defined as SIRS combined with an infectious episode and dysfunction of at least one organ as adapted from the American College of Chest Physicians/Society of Critical Care Medicine consensus conference (16) and age greater than 18 years were included. Patients with burn injuries or who had surgery before consideration were excluded. Healthy volunteers with no previous history during the same period provided blood samples as controls. This study followed the principles of the Declaration of Helsinki and was approved by the institutional review board of Osaka University Hospital. Written informed consent was obtained from all participants or their close relatives.

Blood samples

Blood samples were collected from the trauma patients within 24 h after injury and from the severe sepsis patients within 24 h of the diagnosis to be used as initial biomarkers. TF+/CD13+MPs in the collection tubes containing trisodium citrate (Insepack II-ST; Kyokuto Pharmaceutical Industrial Co, Ltd, Tokyo, Japan) were evaluated by flow cytometry immediately after blood sampling. Serum and plasma samples for measuring concentrations of tumor necrosis factor-α (TNF-α), interleukin 6 (IL-6), soluble TF (sTF), and plasminogen activator inhibitor-1 (PAI-1) were separated and stored at −40°C until the time of the assay.

Analyses of TF+/CD13+MPs

TF+/CD13+MPs in the blood were measured by flow cytometry (BD FACSCanto II; BD Biosciences, San Jose, Calif) and counted by the method we recently reported (17) but with some modifications. In brief, anti-CD146 antibody was changed to anti-CD13 antibody, and the anti-CD141 and anti-CD201 antibodies were removed from the protocol. Blood samples were centrifuged for 5 min at 1,800 × g to remove residual cell debris. Platelet-poor plasma was used for the analysis as previously reported (18, 19). The cell-free supernatant fluid was removed, and the platelet-poor plasma was obtained using a Trucount tube (BD Biosciences) in which 50 μL of platelet-poor plasma and 50 μL of a 5-fold dilution of Binding Buffer (BD Biosciences) and 20 μL of heparin (Novo-Heparin, 5,000 units/5 mL for injection; Mochida Pharmaceutical Co, Tokyo, Japan) were mixed. Then, 2.5 μL each of annexin V, anti-CD13 antibody, and anti-CD142 (TF) antibody (all from BD Biosciences) were added and vortexed. Subsequently, the sample solution was incubated at room temperature for 30 min in the dark. The antigen–antibody reactions were suppressed with the addition of 500 μL of a 10-fold dilution of Binding Buffer (BD Biosciences). Before the analysis, the flow cytometer was calibrated with the use of BD Cytometer Setup and Tracking Beads (BD Biosciences). Measurement of MP diameter was calibrated using reference standard beads (2.00-μm-diameter Fluoresbrite YG carboxylate microspheres; Polysciences Inc, Warrington, Pa). Measurement of the numbers of TF+/CD13+MPs was determined with an automated cell counter (XN9000; Sysmex Corporation, Kobe, Japan) for 5 min.

TF+/CD13+MPs were defined as events detected by annexin V+/CD13+/CD142+ with a diameter of 0.1 to 2.0 μm based on previous reports (20, 21). High-intensity signals caused by antibody aggregation were excluded from the flow cytometry analysis. The platelet counts of the platelet-poor plasma were very low (less than measurement sensitivity, 5 × 103/μL), and the platelet fraction was completely removed with the use of anti-CD13 antibody and anti-CD142 antibody, which do not express on platelets. The formation of MPs was evaluated as the number of TF+/CD13+MPs (Fig. 1).

Fig. 1
Fig. 1:
Representative flow cytometry dot plots of TF+/CD13+MPs in a healthy control subject (A), a patient with trauma (B), and a patient with severe sepsis (C).TF+/CD13+MPs are distinctly immunostained positive for annexin V antibody, anti-CD13 antibody, and anti-CD142 antibody, shown in area Q2 indicated by the ellipse. The counts of TF+/CD13+MPs in the blood are higher in the patients with trauma and severe sepsis than in the healthy control subject.

Analyses of serum levels of TNF-α and IL-6 and plasma levels of sTF and PAI-1

The serum concentrations of TNF-α and IL-6 and plasma concentrations of sTF and PAI-1 were measured with an enzyme-linked immunosorbent assay kit (R&D Systems, Minneapolis, Minn). Frozen samples were thawed and then processed according to the manufacturer's instructions. Absorbance was measured with a microplate reader (SH-9000Lab; Corona Electric Co, Ltd, Ibaraki, Japan). The minimum detectable dose was less than 0.5 pg/mL for TNF-α, 0.70 pg/mL for IL-6, 0.16 pg/mL for sTF, and 0.014 ng/mL for PAI-1.

Definitions of severity and diagnosis of disseminated intravascular coagulation

The Injury Severity Score (ISS) was assessed in trauma patients, and the Acute Physiology and Chronic Health Evaluation (APACHE) II score and the Sequential Organ Failure Assessment (SOFA) score were assessed in both the trauma and severe sepsis patients at the time of enrollment. ISS is the foremost test and gold standard for assessing injury severity. ISS was derived from the Abbreviated Injury Scale score, which was assigned for injuries such as head, face, chest, abdomen, and extremities (including pelvis) (22). The APACHE II score assesses the severity of illness in critically ill patients based on routine physiologic measurements, age, and previous health status and is used to predict the outcome of the critical illness (23). The SOFA score allows calculation of the dysfunction of six organ systems, comprising the respiratory, coagulation, hepatic, cardiovascular, renal and neurologic systems, and the severity of the dysfunction (24).

As defined by the International Society of Thrombosis and Haemostasis (ISTH), disseminated intravascular coagulation (DIC) is a clinical condition characterized by systemic coagulation disorder with loss of localization arising from different causes. It can cause damage to the microvasculature and may produce organ dysfunction (25). In this study, the ISTH overt DIC diagnostic algorithm was used because it has high specificity to ensure an accurate diagnosis of DIC (26). The level of fibrinogen degradation products was used for fibrin-related markers in the ISTH overt DIC criteria and was defined as no increase (0–9 mg/L), moderate increase (10–24 mg/L), or strong increase (>25 mg/L) (27).

Statistical analysis

Continuous variables are expressed as the group median with interquartile range. Steel test was used to assess multiple comparisons using the post hoc Wilcoxon signed-rank test with Bonferroni correction. Correlations between TF+/CD13+MPs and other markers were evaluated with scatter plots and Spearman rank-correlation coefficients. A receiver operating characteristic (ROC) curve was used to evaluate the usefulness of TF+/CD13+MPs as a diagnostic biomarker in critical patients. A value of P <0.05 was considered to indicate statistical significance. Statistical analyses were performed with JMP 11.1.1 for Windows (SAS Institute Inc, Cary, NC).

RESULTS

Patient characteristics

During the study period, 24 trauma patients (47.0 [37.0–63.0] years), 25 severe sepsis patients (69 [58.0–78.0] years), and 23 healthy controls (65.0 [36.0–73.0] years) were included (Table 1). The trauma patients comprised 19 men and 5 women. ISS and the APACHE II and SOFA scores of the trauma patients were 25.0 (16.3–32.8), 11.0 (5.0–15.0), and 2.5 (2.0–4.0), respectively. The causes of trauma were motor vehicle collision (n = 12), fall (n = 11), and penetrating wound (n = 1). The locations of injury were the head (n = 7), face (n = 3), neck (n = 3), thorax (n = 9), abdomen (n = 4), and extremities (n = 7). The severe sepsis patients comprised 15 men and 10 women. The APACHE II, SOFA, and ISTH DIC scores of the sepsis patients were 20.0 (15.0–24.0), 7.0 (3.0–11.0), and 3.0 (2.0–4.0), respectively. The sources of severe sepsis were chest (n = 11), abdomen (n = 3), soft tissue (n = 3), urinary (n = 6), and others (n = 2). None of patients with trauma died. Four patients with severe sepsis died from MOF. The cause of severe sepsis was bacterial infection in all cases. Fifteen gram-positive and 12 gram-negative bacteria were isolated, including 2 mixed bacterial infections. Three positive blood cultures and 24 other site cultures (sputum, pleural fluid, ascites, urine, pus) were identified. There were no significant differences between the trauma patients, severe sepsis patients, and healthy controls in regard to age and sex.

Table 1
Table 1:
Patient characteristics

Numbers of TF+/CD13+MPs

In the overall analysis of the study participants, the numbers of TF+/CD13+MPs were significantly increased in the trauma patients compared with those in the healthy controls (Fig. 2). Similarly, there was a significant difference between the severe sepsis patients and the healthy controls (Fig. 2).

Fig. 2
Fig. 2:
The numbers of TF+/CD13+MPs in the patients with trauma and severe sepsis.The boxes indicate the lower and upper quartiles, the central dark line is the median, and the ends of the whiskers indicate the maximum and minimum values. Asterisks indicate a statistically significant (P <0.05) difference between groups.

Correlations between TF+/CD13+MPs and severity of illness in the trauma and severe sepsis patients

We assessed the correlation between the number of TF+/CD13+MPs and the disease severity scoring systems (ISS, APACHE II, and SOFA) in the trauma and severe sepsis patients. In the trauma patients, significant correlations were found between the number of TF+/CD13+MPs and the ISS and the APACHE II score, but no significant correlations were found between the number of TF+/CD13+MPs and the SOFA score (Fig. 3, A–C). In the severe sepsis patients, significant correlations were found between the number of TF+/CD13+MPs and the APACHE II score, but no significant correlations were found between the number of TF+/CD13+MPs and the SOFA score (Fig. 4, A and B).

Fig. 3
Fig. 3:
Correlations between TF+/CD13+MPs and severities and biochemical parameters in the patients with trauma.APACHE II score (A), SOFA score (B), ISS (C), IL-6 (D), and PAI-1 (E). APACHE indicates Acute Physiology and Chronic Health Evaluation; IL-6, interleukin 6; ISS, Injury Severity Score; PAI-1, plasminogen activator inhibitor-1; SOFA, Sequential Organ Failure Assessment.
Fig. 4
Fig. 4:
Correlations between TF+/CD13+MPs and severities and biochemical parameters in the patients with severe sepsis.APACHE II score (A), SOFA score (B), ISTH DIC score (C), IL-6 (D), and PAI-1 (E). APACHE indicates Acute Physiology and Chronic Health Evaluation; IL-6, interleukin 6; SOFA, Sequential Organ Failure Assessment.

Correlations between TF+/CD13+MPs and ISTH DIC score in the severe sepsis patients

To investigate the association between the number of TF+/CD13+MPs and systemic coagulant activity, the ISTH DIC score was evaluated in the severe sepsis patients. In these patients, the numbers of TF+/CD13+MPs increased significantly with the increase of the ISTH DIC score (Fig. 4C).

Correlations between TF+/CD13+MPs and biochemical parameters in the trauma and severe sepsis patients

To assess the association between the number of TF+/CD13+MPs and systemic inflammatory markers, the levels of TNF-α and IL6 were measured. Significant correlations were found between the number of TF+/CD13+MPs and IL6 levels (Figs. 3 and 4) but not between the number of TF+/CD13+MPs and TNF-α levels (P = 0.766, rho = 0.064; P = 0.361, rho = 0.195; respectively) in both the trauma and severe sepsis patients. To study the relation between the number of TF+/CD13+MPs and coagulative factor, the levels of sTF were measured. There were no significant correlations between the number of TF+/CD13+MPs and sTF (P = 0.102, rho = −0.342; P = 0.991, rho = −0.002; respectively) in both the trauma and severe sepsis patients. To assess the systemic endothelial damage, the levels of PAI-1 were evaluated. The number of TF+/CD13+MPs showed a tendency to correlate with PAI-1 levels in the trauma patients (Fig. 3), but there was no statistically significant correlation between the number of TF+/CD13+MPs and PAI-1 levels in the severe sepsis patients (Fig. 4).

Cut-off values of TF+/CD13+MPs for the diagnosis of critical patients with trauma and severe sepsis

The patients were divided into the following two groups on the basis of expected mortality: critical patients with trauma (ISS ≥25) and non-critical patients (ISS ≤24) (28), and critical patients with severe sepsis (APACHE II score ≥25, SOFA score ≥12) and non-critical patients (APACHE II score ≤24, SOFA score ≤11) (29, 30). In the model using ISS to diagnose the critical patients with trauma, the cut-off value of TF+/CD13+MPs was 9245/mL blood with an area under the curve (AUC) of 0.82. In the model using the APACHE II and SOFA scores to diagnose critical patients with severe sepsis, the cut-off values of TF+/CD13+MPs were 9245/mL blood with an AUC of 0.73 and 11,916/mL blood with an AUC of 0.83, respectively (Table 2).

Table 2
Table 2:
Cut-off values of TF+/CD13+MPs for the diagnosis of critical patients with trauma and severe sepsis

DISCUSSION

This is the first study, to our knowledge, to evaluate the association between TF+/CD13+MPs and the pathogenesis of early SIRS following trauma and sepsis. The aim of this study was to investigate the usefulness of TF+/CD13+MPs as a biomarker for inflammation and severity in the early pathogenesis of SIRS following trauma and sepsis. The numbers of TF+/CD13+MPs significantly increased in both trauma and severe sepsis. This suggests that activated monocytes upregulate the expression of TF and produce TF+/CD13+MPs in the acute phase of trauma and severe sepsis.

In this study, the numbers of TF+/CD13+MPs significantly correlated with ISS in the trauma patients. ISS is a quantitative measure of anatomic tissue injury severity that provides an overall score for patients with multiple injuries. Previously, Park et al. (31) showed that annexin V-positive MPs correlated significantly with ISS in trauma patients, suggesting that there might be an association between MPs and tissue injury severity. Tissue injury leads to the release of damage-associated molecular patterns (DAMPs). Levels of DAMPs are related to the extent of tissue injury (32). Pattern recognition receptors such as Toll-like receptors on immune cells including monocytes respond to DAMPs and activate the immune cells. Our data suggest that monocyte activation is enhanced in accordance with the severity of tissue injury, leading to the expression of TF and production of TF+/CD13+MPs in the acute phase of trauma.

Our data demonstrated that the numbers of TF+/CD13+MPs significantly correlated with the levels of IL-6, a systemic inflammatory marker, and the APACHE II score, which reflects physiological severity in trauma patients. The numbers of TF+/CD13+MPs also significantly correlated with the IL-6 levels and APACHE II score in severe sepsis patients. These findings indicate that activated monocytes upregulate the expression of TF and promote the generation of TF+/CD13+MPs, thus causing the acute systemic inflammation and exacerbating the physiological pathogenesis in the acute phase of trauma and severe sepsis.

In our study, the numbers of TF+/CD13+MPs correlated significantly with the ISTH DIC score in the severe sepsis patients. Sepsis-induced DIC is basically triggered by the release of blood-borne TF, which is present in three forms referred to as MP-borne TF, sTF, and cell-borne TF (33). It was reported that TF dependent on MPs shows significantly higher procoagulant activity than TF independent of MPs in vitro(11). Furthermore, we recently reported that TF-positive endothelial MPs are associated with the pathogenesis of sepsis-induced DIC (17). Therefore, our results suggest that the excessive production of TF+/CD13+MPs might cause harmful microthrombi leading to the progression of sepsis-induced DIC.

Our study clearly demonstrated that TF+/CD13+MPs correlated with severity in the acute phase of trauma and severe sepsis in the study patients. Both the ROC analysis using the ISS for critical patients with trauma and the SOFA score for critical patients with severe sepsis showed high diagnostic values (AUC >0.8). This suggests that the measurement of TF+/CD13+MPs might be useful as a biomarker for the assessment of disease severity in the pathogenesis of early SIRS following trauma and severe sepsis. Interestingly, recent articles reported CD13 to be a specific adhesion molecule involved in monocyte-endothelial cell adhesion, suggesting that TF+/CD13+MPs could be used to evaluate monocyte-endothelial cell adhesion in the early phase of SIRS following trauma and sepsis. CD13 is also expressed on renal tubular cells (34), indicating that increased numbers of TF+/CD13+MPs might be used as a biomarker of acute renal injury in the early phase of SIRS following trauma and sepsis.

Because the inclusion criteria for severe sepsis in this study are different from the latest criteria defined by Sepsis-3 (35), we reanalyzed our data using the Sepsis-3 criteria. The results showed almost the same tendency as those of this study using the previous criteria (see Supplemental Digital Contents Table 1, http://links.lww.com/SHK/A487, which shows patient characteristics), (see Supplemental Digital Content Fig. 1, http://links.lww.com/SHK/A488, which shows the numbers of TF+/CD13+MPs), (see Supplemental Digital Content Fig. 2, http://links.lww.com/SHK/A489, which shows the correlations between TF+/CD13+MPs and severities and biochemical parameters) (see Supplemental Digital Contents Table 2, http://links.lww.com/SHK/A487, which shows cut-off values of TF+/CD13+MPs for the diagnosis of critical patients).

As limitations of this study, the numbers of patients and controls were relatively small, and the data were collected at a single institution. Also, because the mortality rates were low (0% and 16% in the trauma and severe sepsis patients, respectively), prognostic factors could not be analyzed in this study. Second, we evaluated the change in TF+/CD13+MPs at only one time point, and there was no follow-up evaluation to assess the chronological changes of TF+/CD13+MPs. Third, the specific bioactivity of TF+/CD13+MPs was not elucidated in this study. Thus, further studies are needed to assess the association between TF+/CD13+MPs and the pathogenesis of trauma and severe sepsis.

CONCLUSIONS

This study is the first report to show that increased numbers of TF+/CD13+MPs were significantly correlated with disease severity in the acute phase of SIRS in patients with trauma or severe sepsis. Our findings suggest that the evaluation of the number of TF+/CD13+MPs might be useful as a biomarker for severity in patients in the early phase of SIRS following trauma and sepsis.

Acknowledgments

The authors thank Tomomi Yamada (Department of Clinical Epidemiology and Biostatistics, Osaka University Graduate School of Medicine) for support with the statistical analysis. The authors are grateful to the patients and their families for their trust, and to the healthy controls.

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Keywords:

Annexin V; CD13 antigen; CD142 antigen; interleukin-6; plasminogen activator inhibitor 1

Supplemental Digital Content

© 2017 by the Shock Society