Skip to main content
Download PDF

A single-center study of reference intervals for TAT, PIC, TM and t-PAIC in healthy older Chinese adults

Thrombosis Journal volume 22, Article number: 82 (2024) Cite this article

Abstract

Objective

To explore the distribution of thrombin–antithrombin complex (TAT), plasmin-α2-antiplasmin inhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) in healthy older Chinese adults, and establish the reference intervals (RIs).

Methods

The Biotech Shine i2900 chemiluminescence immune assay was used to measure the plasma concentrations of TAT, PIC, TM, and t-PAIC in 1628 adults ≥ 60 years. The RIs were established using the 2.5th and 97.5th percentiles of the distribution.

Results

TAT levels were lower in males than females across all ages. Differences between the ages of 60–79 and ≥ 80 in both sex groups were statistically significant, with an upward trend with age. PIC levels showed no difference between the sexes but increased with age in both groups. TM levels did not differ between the sex groups, with slight fluctuation with age. The level in females aged 60–69 was slightly higher than that in the other groups; the difference was statistically significant. T-PAIC levels were not significantly different between the sex groups, with less fluctuation with sex and age. The level in males ≥ 80 years old was slightly lower than that in the other groups; the difference was statistically significant. The RIs for all markers in healthy older Chinese adults were determined and statistically reported by age and sex. For TAT, the RIs for males aged 60–79 and ≥ 80 are 0.51–2.30 ng/mL and 0.88–3.72 ng/mL, respectively, whereas for females aged 60–79 and ≥ 80, the RIs are 0.68–2.82 ng/mL and 1.02–3.67 ng/mL, respectively. For PIC, the RIs for the age groups 60–69, 70–79, and ≥ 80 are 0.10–0.89 µg/mL, 0.12–1.00 µg/mL, and 0.21–1.04 µg/mL, respectively. The RI of TM for females aged 60–69 is 3.32–13.22 TU/mL, whereas it is 2.96–13.26 TU/mL for the other groups. The RI of t-PAIC for males aged ≥ 80 is 1.63–10.68 ng/mL, whereas it is 2.33–11.34 ng/mL for the other groups.

Conclusions

Discrepancies exist in thrombus markers among different sex and age groups. The RIs of TAT, PIC, TM and t-PAIC for healthy older Chinese adults were successfully established.

Introduction

Thromboembolism has accounted for a quarter of the total number of global deaths since 2010 [1]. With the continuing development of the social economy, changes in lifestyle, and population aging in China [2], thrombotic diseases have become a major threat to the health of residents. Compared to young and middle-aged people, older adults are more prone to slow blood flow and a hypercoagulable state due to physiological changes in vascular structure and function, increased coagulation factors, and changes in platelet (PLT) function, which can lead to thrombosis [3]. Moreover, some older patients are prone to deep vein thrombosis (DVT) due to long-term bed rest, which can lead to pulmonary embolism (PE). Older people are also at high risk of venous thromboembolism (VTE) [4, 5]. Currently, there are approximately 280 million older adults (aged 60 and above) in China [6], comprising approximately a quarter of the global older adult population. Therefore, strengthening the early prevention of thrombosis in older adults has important clinical significance and social value.

At present, measurement of conventional coagulation markers such as prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), and coagulation factor screening is primarily focused on the prevention of bleeding but is insensitive to the early state of thrombosis. D-dimer detection and imaging technologies, which include duplex ultrasound, computed tomography, magnetic resonance imaging, and arteriography [7], are widely used in the evaluation of suspected VTE of the lower extremities. D-dimer is a marker of endogenous fibrinolysis and can be detected in patients with VTE. Moreover, several studies have shown that the D-dimer assay has a high negative predictive value and is a sensitive but non-specific marker of VTE [8]. Some research suggests that normal D-dimer levels can exclude VTE in low risk patients without the need for additional investigation [9]. However, D-dimer cannot predict the early state of thrombosis. Although imaging examination is the gold standard for determining thrombosis [10], some patients with thrombosis may experience delayed symptoms, and imaging cannot always detect early thrombosis. Additionally, studies have shown that some blood vessels, such as the iliac vein and vena cava, are not well displayed on ultrasound; however, these vessels are significant sources of PE [11]. The current widely used examination methods are unable to determine whether patients have a tendency to thrombosis formation, and some blood vessels are prone to thrombosis, which can be difficult to accurately diagnose. In recent years, thrombus markers such as thrombin–antithrombin complex (TAT), plasmin-α 2-antiplasmin inhibitor complex (PIC), thrombomodulin (TM), and tissue plasminogen activator-inhibitor complex (t-PAIC) have been found to be highly sensitive to the formation of thrombosis and can indicate the early stage of risk.

TAT is formed by a 1:1 combination of thrombin and its inhibitor, antithrombin (AT). Under physiological conditions, thrombin is produced in low amounts and exists for an extremely short period of time in the body. TAT marks the early initiation of the coagulation pathway and can directly and sensitively reflect the activation degree of the coagulation system [12, 13]. Song’s research [14] shows that the TAT level of patients with ischemic stroke is significantly higher than that of healthy people. Additionally, the level of TAT differs in cardiogenic, lacunar, and atherosclerotic stroke, and it significantly increases in various stages and the acute state of cardiogenic stroke. Moreover, the efficacy of TAT measurement in evaluating coagulation status in sepsis is superior to traditional coagulation indicators [15], and TAT significantly decreases after intravenous heparin treatment, making it a suitable evaluation indicator for anticoagulant therapy [16].

PIC is produced by the combination of fibrinolytic enzyme and its specific inhibitor (α2-antiplasmin, α2-PI) and indicates the early initiation of the fibrinolytic system [17]. In general, the fibrinolytic system is activated immediately after the coagulation system is started; hence, the increase in PIC indicates an increase in the activity of the fibrinolytic system, providing evidence of thrombosis formation. Studies have shown that the level of PIC in patients with malignant tumors is higher than that in patients with benign tumors, and the accuracy of predicting and diagnosing malignant tumors is higher than that of D-dimer [18].

During the process of thrombosis, vascular endothelial cells are disrupted and abnormally secrete a transmembrane glycoprotein TM into the bloodstream, leading to an increase of TM concentration in plasma. Therefore, the level of TM can be used as a sensitive index to evaluate the severity of vascular endothelial injury and disease [19]. Monitoring TM concentration in blood has clinical significance in the prognostic evaluation of cardiovascular diseases, diabetes, and ischemic and inflammatory endothelial injury [20,21,22].

T-PAIC is formed by a 1:1 combination of tissue-type plasminogen activator (t-PA) and physiological inhibitor plasminogen activator-inhibitor-1 (PAI-1) in vascular endothelial cells. PAI is a specific inhibitor of PA, which plays a role in regulating the fibrinolytic system, reflecting the degree of fibrinolytic inhibition [23]. These four thrombus markers have been used as predictors of postoperative thrombosis in patients with lung cancer [24]. Zhou’s research [25] indicates that the levels of TAT, PIC, TM, and t-PAIC are significantly increased in these patients, and the combination of fibrin/fibrinogen degradation products (FDP) and D-dimer has a high sensitivity and specificity for the diagnosis of malignant tumors. Moreover, the increased level of the new biomarkers is negatively correlated with patient survival.

Owing to the coexisting characteristics of multiple diseases, multiple syndromes, and multiple medications in older people, their clinical diagnosis differs from those of other age populations, and the RIs also differ. The RI is an important tool to help clinicians understand laboratory results and determine whether patients need further treatment [26]. Therefore, it is necessary to establish the RIs for these thrombus markers in older adults, but there presently is no such research in China. Therefore, the purpose of this study was to establish the RIs for these markers in older people of different sexes and age groups and to explore the correlation with some potential influencing factors and other laboratory indicators in order to provide a basis for clinical diagnosis and treatment.

Materials and methods

Participants

A total of 1628 individuals aged ≥ 60 years with apparent health who underwent physical examinations at the Health Management Center of Beijing Anzhen Hospital from January 2023 to April 2024 were selected. According to the World Health Organization’s definition of older adults in underdeveloped countries, people over 60 years old were included and divided into three groups in the study: 60–69 years old, 70–79 years old, and ≥ 80 years old. The study further divided the participants into six subgroups according to sex.

Inclusion criteria were as follows: All participants completed questionnaires and signed informed consent forms. The definition of apparent healthy older people refers to the Chinese standard for healthy older adults issued by the National Health Commission on September 28, 2022, and implemented on March 1, 2023: (1) Age ≥ 60 years; (2) Age-related changes in important organs did not lead to functional abnormalities and major diseases, and relevant high-level factors were controlled within the age-appropriate range, indicating a certain level of disease resistance; (3) Cognitive function is basically normal, can adapt to the environment, be optimistic and positive, self-satisfied, or self-evaluated well; (4) Normal daily activities, self-care or basic self-care; (5) Blood pressure < 140/90 mmHg, and in older adults (≥ 80 years) not lower than 120/60 mmHg; (6) Body mass index (BMI) of 18.0–28.0 kg/m2; (7) Normal coagulation-related indicators; (8) Glycated hemoglobin A1c (HbA1c) in older individuals is 5.0–6.5% for those with normal blood glucose levels; in diabetes patients (without chronic complications of diabetes) it is 6.0–7.0%; (9) Cholesterol (TC): 3.1–6.2 mmol/L, triglycerides (TG): 0.8–2.3 mmol/L, low-density lipoprotein cholesterol (LDL-C): 1.8–3.9 mmol/L, high-density lipoprotein cholesterol (HDL-C) > 1.0 mmol/L.

Exclusion criteria: (1) History of hospitalization or serious illness within the past six months; (2) have taken anticoagulants, antiplatelet drugs, and other drugs that affect the coagulation and fibrinolysis system within three months, including but not limited to agents such as warfarin, aspirin, clopidogrel, new oral anticoagulants, or heparin; (3) history of surgery or blood donation within three months; (4) fever or antibiotic use in the past two weeks; (5) family history of bleeding or coagulation disorder, hematologic system diseases, severe cardiovascular or cerebrovascular diseases, liver or kidney insufficiency, autoimmune system diseases, or malignant tumor; (6) smoking volume ≥ 20 cigarettes per day; and (7) alcoholism.

Sample collection

All participants fasted for at least eight hours. The next morning, 2.7 mL of venous blood was collected using a BD vacuum blood collection tube containing 109 mmol/L citrate anticoagulant, with anticoagulant-to-blood volume ratio of 1:9. The deviation in blood collection was less than 10%. The samples were immediately gently mixed three to six times to ensure a full mixture with the anticoagulant.

Samples were centrifuged at 3000 RCF at 26 °C for 15 min, and 500 µL of plasma was transferred into an Eppendorf tube, then numbered and stored at -80 °C. After all the required samples were collected, the concentrations of TAT, PIC, TM, and t-PAIC were detected, and the qualified subjects were recorded and screened according to the determination results. The samples could only be frozen and thawed once.

Laboratory analysis

The Biotech Shine i2900 (Guangzhou Wondfo Biotech Co., Ltd.) automated chemiluminescence immune detection system was used to process all assays (TAT, PIC, TM, and t-PAIC). The testing reagents, calibrators, and quality controls for the four thrombus markers were all sourced from the same manufacturer, Wondfo Biotech Co., Ltd. The calibrators were supplied with the kits and traceable to an internal reference substance, whereas the internal quality controls are independently certified in China. The analyzer was subjected to regular calibration and maintenance in accordance with the manufacturer’s instructions. Daily quality control measures were implemented to ensure precision, and all tests were conducted following standard operating procedures. Before testing, the samples were placed in a 37 °C water bath for rapid re-dissolution and mixed thoroughly. The coefficient of variation for both intra-assay and inter-assay of the four assays was maintained at less than 5%.

Statistical analysis

SPSS 27.0 statistical software was used for analysis. According to the CLSI C28-A3, we used a box diagram to identify and eliminate outliers (values outside Q1–1.5 × IQR and Q3 + 1.5 × IQR were considered outliers, IQR = Q3-Q1). Continuous variables of non-normal distribution were expressed by M (Q1, Q3). The Mann–Whitney U test was used for comparison between the two groups, and the Kruskal–Wallis H-test was used for comparison among multiple groups; P < 0.05 was considered to indicate statistical difference. The RIs of TAT, PIC, TM, and t-PAIC were established using nonparametric tests with the 2.5th and 97.5th percentile. Spearman correlation analysis was used to determine the correlation between the levels of these markers and their potential influencing factors. These factors were available for all participants as part of their routine check, with no missing values.

Results

General information of research subjects

The characteristics of a total of 1628 eligible individuals for health examinations were collected, including 778 males and 850 females. The general information on the research subjects is shown in Supplemental Table 1.

Comparison of TAT, PIC, TM, and t-PAIC among subjects by sex

Overall data distribution of thrombus markers

The data distribution of thrombus markers after outliers were eliminated by the box diagram method is shown in Fig. 1. Specifically, 10, 5, 6, and 7 outliers were excluded from the TAT, PIC, TM and t-PAIC groups, respectively. The level of TAT in males was lower than that in females, and the difference was statistically significant (P < 0.05). There was no significant difference in PIC, TM, and t-PAIC between males and females (P values were 0.43, 0.14, and 0.07, respectively) (Supplemental Tables 2 and Fig. 2).

Fig. 1
figure 1

Overall data distribution of thrombus markers

Note: A, B, C, and D represent the overall distribution data for TAT, PIC, TM, and t-PAIC, respectively. The bold horizontal line in the middle represents the median, whereas the upper and lower horizontal lines are P25 and P75, respectively

Full size image
Fig. 2
figure 2

Data distribution of thrombus markers by sex

Note: A, B, C, and D represent the distribution of data by sex of TAT, PIC, TM, and t-PAIC, respectively. The bold horizontal line in the middle represents the median, whereas the upper and lower horizontal lines reflect P25 and P75, respectively

Full size image

Comparison of thrombus markers among different ages and sexes

The level of TAT in each age group was influenced by sex, and the difference was statistically significant (P < 0.01). PIC was not affected by sex in each age group, and the difference was not significant (P values were 0.923, 0.563, and 0.303, respectively). The TM level was influenced by sex for those in the range of 60–69 years old (P < 0.01), whereas the t-PAIC level was influenced by sex in the age range ≥ 80 years old (P = 0.02) (Table 1).

Table 1 Comparison of thrombus markers among different ages and sexes [M (Q1, Q3)]
Full size table

Comparison of TAT, PIC, TM, and t-PAIC in different age groups

Comparison of Thrombus markers by sex in different age groups

The differences in markers between males and females in different age groups (60–69 years old, 70–79 years old, ≥ 80 years old) were compared. The TAT level of each age group was compared between males and females, and the difference was statistically significant (P < 0.01). The mean TAT level of males in each age group was lower than that of females (P < 0.01), and the overall level increased with age. The PIC levels of different age groups were compared between males and females, and the difference was statistically significant (P < 0.01) and increased with age. The TM was relatively stable, with a higher level in the female group aged 60–69 compared to that in other groups (P < 0.01). Similarly, the t-PAIC was relatively stable, with a lower level in the male group age ≥ 80 compared to that in other groups (P < 0.01) (Supplemental Tables 3 and Fig. 3).

Fig. 3
figure 3

Dot plot of the distribution of thrombus markers with age

Note : A, B, C, and D reflect the data distribution of TAT, PIC, TM, and t-PAIC with age, respectively

Full size image

Pairwise comparison of thrombus markers by sex in age groups

There was no significant difference in the level of TAT between ages 60–69 years and 70–79 years in the male and female group (P values were 0.29 and 0.45, respectively), but there were significant differences between ages 60–79 years and ≥ 80 years (P < 0.05). The PIC levels of each age group were compared pairwise between males and females, and the differences were statistically significant (P < 0.05). There was no significant difference in TM levels among male age groups (P values were 0.99, 0.68, and 0.59, respectively). There were differences between the 60–69 years old and 70–79 years old groups, as well as the ≥ 80 years old group in females (P < 0.05), whereas there was no difference between the 70–79 years old and ≥ 80 years old groups (P = 0.19). There was no statistically significant difference in t-PAIC levels among different age groups in females (P values were 0.55, 0.11, and 0.25, respectively). There were differences between the ≥ 80 years old and the 60–69 years old groups, as well as the 70–79 years old group in males (P < 0.05), whereas there was no difference between the 60–69 years old and the 70–79 years old groups (P = 0.58) (Supplemental Tables 4 and Fig. 4).

Fig. 4
figure 4

Comparison of thrombus markers by age. A-H represent the comparison of TAT, PIC, TM and t-PAIC by age in different gender groups, respectively. The upper and lower edges of the box plot represent the P75 and P25, respectively. The horizontal line in the middle of each box plot reflects the median, whereas the upper and lower horizontal lines reflect the P97.5 and P2.5, respectively.

Note : The upper and lower edges of the box plot represent the P75 and P25, respectively. The horizontal line in the middle of each box plot reflects the median, whereas the upper and lower horizontal lines reflect the P97.5 and P2.5, respectively

Full size image

Establishment of the RIs

Based on the above results, the groups with no difference were merged to obtain an RI, represented by M (P2.5, P97.5). The RI of TAT for males was 0.51–2.30 ng/mL for ages 60–79, 0.88–3.72 ng/mL for ages ≥ 80, and for females it was 0.68–2.82 ng/mL for ages 60–79, and 1.02–3.67 ng/mL for ages ≥ 80. The RI of PIC was 0.10–0.89 µg/mL for ages 60–69, 0.12–1.00 µg/mL for ages 70–79, and 0.21–1.04 µg/mL for ages ≥ 80. The RI of TM was 3.32–13.22 TU/mL for females aged 60–69 and 2.96–13.26 TU/ml for the other groups. The RI of t-PAIC was1.63-10.68 ng/mL for males aged ≥ 80 and 2.33–11.34 ng/mL for the other groups (Table 2).

Table 2 95% RIs of thrombus markers for healthy older adults
Full size table

Verification of the RIs

Adopting the same inclusion and exclusion methods for the older population as used when establishing the RIs previously, an additional 20 independent samples were collected for validation testing in each RI, and the results were all within the ranges we created (Table 3), indicating that the RIs for TAT, PIC, TM, and t-PAIC established in this study for different ages and sexes are suitable for the older population.

Table 3 Validation results of RIs for thrombus markers in healthy older adults
Full size table

Correlation analysis between Thrombus markers and potential influencing factors

Selecting indicators that may have potential associations with thrombus markers for correlation analysis (Supplemental Table 5), the results showed that TAT was correlated with age, BMI, red blood cell (RBC), and D-dimer (P < 0.05); PIC was correlated with age, alanine aminotransferase (ALT), total bilirubin (TBIL), direct bilirubin (DBIL), creatinine (Cr), uric acid (UA), triglyceride cholesterol (TG), white blood cell (WBC), hemoglobin (HGB), and D-dimer (P < 0.05); TM was correlated with aspartate aminotransferase (AST), TG, LDL-C, and D-dimer (P < 0.05); and t-PAIC was correlated with ALT, fasting blood glucose (FBG), TG, HDL-C, WBC, RBC, and PLT (P < 0.05).

Discussion

According to research, the incidence of VTE in adults over 65 years old had reached approximately 3% in 2004 and increased year by year, especially with an increase in age, and approximately 40% of VTE cases were caused by hospitalization [3, 27]. Therefore, the prevention and treatment of cardiovascular diseases and thrombotic diseases of older people have been the focus of social medical care in the past decade. In order to better serve society, it is necessary to improve the efficacy of early prevention measures and the clinical diagnosis and treatment of thrombosis. Monitoring the level of thrombus markers in inpatients is of great clinical significance in evaluating the likelihood of developing VTE and subsequent treatment efforts.

These thrombus markers have been gradually recognized clinically as offering significant advantages in diagnosis and treatment evaluation. The combined monitoring of TAT and D-dimer has clinical significance in distinguishing varicose vein disease from DVT, with a sensitivity of 100% and specificity of 79% for DVT. Therefore, patients who are negative for both can undergo varicose vein surgery without the need for a vascular imaging examination [28]. The levels of TAT and PIC significantly increased in disseminated intravascular coagulation (DIC) before and after the onset of the disease [29], and their combined ratio can be used as an indicator to evaluate the prognosis of patients with DIC [17]. TM can be used to monitor DIC and multiple organ dysfunction syndromes in patients with sepsis [30].

Our study found that the levels of TAT and PIC increase with age, which is consistent with the physiological changes of enhanced coagulation function in older adults. Researches by Öhlin and others [31,32,33] have shown that TM mainly exerts anticoagulant effects by activating the protein C system to capture thrombin. Therefore, when the coagulation system is activated or more active, TM will exist as a complex in blood, and its concentration will decrease, which is consistent with the finding in this study that TM levels decrease slightly with age. T-PAIC is a complex that is dominated by PAI-1 and reflects the degree of fibrinolysis inhibition of the body. It is produced by the 1:1 combination of PAI-1 and t-PA [34, 35]. Our results found that t-PAIC decreases slightly with age, which is consistent with the increasing trend of PIC with age. Therefore, the trend change of t-PAIC results in this study is in line with expectations. At present, research on the RIs of these thrombus markers for pregnant women is gradually maturing [36,37,38]. According to Wu’s study [36], the levels of TAT, PIC, and t-PAIC increased from trimester one to trimester three, whereas PIC remained stable during all trimesters. However, there are currently no reports on the RIs of these markers for either the older or the younger populations.

To ensure the reliability and accuracy of the results in this study, plasma was quickly separated and stored within two hours after sample collection. According to Chen et al. [12], TAT, PIC, TM, and t-PAIC were validated to remain stable within eight hours at room temperature. In addition, the chemiluminescence immune detection method has higher specificity and sensitivity than the traditional ELISA method [39, 40]. Compared with the RIs provided by the manufacturer’s manual, which are based on data from the entire age group, the RI of TAT obtained in our study was narrower than that provided by the manual (TAT < 4.0 ng/mL). The upper limit of the RI for PIC was higher than that provided by the manual (PIC < 0.85 µg/mL) and increased with age. These differences may be attributed to the geography, race, sex, age and sample size of the enrolled population. In our study, 1628 healthy participants over 60 years old were enrolled, whereas 279 healthy participants aged 17–80 years old were enrolled in the manufacturer’s RI study. Therefore, it is reasonable that there are differences between them. Meanwhile, the RIs of TM and t-PAIC were not significantly different from those provided by the manual (TM: 3.82–13.35 TU/mL, t-PAIC: 0-10.52 ng/mL).

This study preliminarily analyzed the correlation between biomarkers and their potential influencing factors. The results showed a positive correlation between age and TAT, as well as PIC, which may be related to the activation of coagulation function caused by aging. Multiple studies have shown that plasma D-dimer levels increase with age, and it is recommended to use age-corrected cut-off values for negative exclusion of VTE in patients over 50 years old [41, 42]. However, both TAT and PIC are positively correlated with D-dimer, which may indicate that TAT and PIC are early markers of activation of the coagulation and fibrinolysis systems in the body, whereas D-dimer appears later, indicating a causal and inheritance relationship throughout the entire system. The influencing factors and associated indicators of thrombus markers require further in-depth research in the future.

Owing to the differences in lifestyle and physical functions between older and middle-aged or young people, the clinical diagnosis and evaluation for older people requires the use of RIs established by relevant populations. The results obtained in this study have been verified, and it can be considered that the RIs established for older adults are reliable and feasible, and there are certain differences from those established for all ages. Our study has limitations. It was a single-center study; hence, the sample size was not large enough, and potential differences exist in lifestyle and dietary habits among the population. Therefore, it is recommended that laboratories in different regions should establish their own RIs according to each situation. Our results can provide a reference for other laboratories but will need to be verified locally.

Conclusions

This study established the RIs of TAT, PIC, TM, and t-PAIC in different sex and age groups for the first time in China, providing a basis for better application of these thrombus markers to clinical practice, and also conducting empirical exploration for the establishment of multi-center RIs for the older adult population.

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

TAT:

Thrombin–antithrombin Complex

PIC:

Plasmin-α2-antiplasmin Inhibitor Complex

TM:

Thrombomodulin

t-PAIC:

Tissue Plasminogen Activator-inhibitor Complex

RIs:

Reference Intervals

DVT:

Deep Vein Thrombosis

PE:

Pulmonary Embolism

VTE:

Venous Thromboembolism

PT:

Prothrombin Time

APTT:

Activated Partial Thromboplastin Time

FIB:

Fibrinogen

AT:

antithrombin

α2-PI:

α2-antiplasmin

t-PA:

Tissue-type plasminogen Activator

PAI-1:

Physiological inhibitor Plasminogen Activator-inhibitor-1

FDP:

Fibrin/Fibrinogen Degradation Products

DIC:

Disseminated Intravascular Coagulation

HbA1c:

Glycated Hemoglobin A1c

BMI:

Body Mass Index

ALT:

Alanine Aminotransferase

AST:

Aspartate Aminotransferase

TBIL:

Total Bilirubin

DBIL:

Direct Bilirubin

Cr:

Creatinine

UA:

Uric Acid

FBG:

Fasting Blood Glucose

TC:

Total Cholesterol

TG:

Triglyceride Cholesterol

HDL-C:

High-Density Lipoprotein-Cholesterol

LDL-C:

Low-Density Lipoprotein-Cholesterol

WBC:

White Blood Cell

RBC:

Red Blood Cell

HGB:

Hemoglobin

PLT:

Platelet

References

  1. Wendelboe AM, Raskob GE. Global burden of thrombosis epidemiologic aspects. Circ Res. 2016;118(9):1340–7.

    Article  CAS  PubMed  Google Scholar 

  2. Mackman N, Bergmeier W, Stouffer GA, Weitz JI. Therapeutic strategies for thrombosis: new targets and approaches. Nat Rev Drug Discov. 2020;19(5):333–52.

    Article  CAS  PubMed  Google Scholar 

  3. Stuby J, Haschke M, Tritschler T, Aujesky D. Oral anticoagulant therapy in older adults. Thromb Res. 2024;238:1–10.

    Article  CAS  PubMed  Google Scholar 

  4. Wolberg AS, Rosendaal FR, Weitz JI, Jaffer IH, Agnelli G, Baglin T, et al. Venous thrombosis. Nat Rev Dis Primers. 2015;1:15006.

    Article  PubMed  Google Scholar 

  5. Sepúlveda C, Palomo I, Fuentes E. Mechanisms of endothelial dysfunction during aging: predisposition to thrombosis. Mech Ageing Dev. 2017;164:91–9.

    Article  PubMed  Google Scholar 

  6. The Central People’s Government of the People’s Republic of China. 2022 National Aging Development Bulletin. [2023-12-14]. https://www.gov.cn/lianbo/bumen/202312/content_6920261.htm

  7. Orbell JH, Smith A, Burnand KG, Waltham M. Imaging of deep vein thrombosis. Br J Surg. 2008;95(2):137–46.

    Article  CAS  PubMed  Google Scholar 

  8. Wells PS, Anderson DR, Rodger M, Forgie M, Kearon C, Dreyer J, et al. Evaluation of D-dimer in the diagnosis of suspected deep-vein thrombosis. N Engl J Med. 2003;349(13):1227–35.

    Article  CAS  PubMed  Google Scholar 

  9. Zhang DD, Li FF, Du XW, Zhang XY, Zhang ZH, Zhao WY, et al. Diagnostic accuracy of biomarker D-dimer in patients after stroke suspected from venous thromboembolism: a diagnostic meta-analysis. Clin Biochem. 2019;63:126–34.

    Article  CAS  PubMed  Google Scholar 

  10. Naeem Khan MN, Ahmed A, Zafar I, Akhtar S, Aurangzeb MH, Khan A. The diagnostic accuracy of Carotid Doppler in detecting anechoic Thrombus against CT angiography as the Gold Standard. Cureus. 2022;14(7):e26951.

    PubMed  PubMed Central  Google Scholar 

  11. Loud PA, Katz DS, Klippenstein DL, Shah RD, Grossman ZD. Combined CT venography and pulmonary angiography in suspected thromboembolic disease: diagnostic accuracy for deep venous evaluation. AJR Am J Roentgenol. 2000;174(1):61–5.

    Article  CAS  PubMed  Google Scholar 

  12. Chen Q, Shou W, Wu W, Wang G, Cui W. Performance evaluation of thrombomodulin, thrombin-antithrombin complex, plasmin-α2-antiplasmin complex, and t-PA: PAI-1 complex. J Clin Lab Anal. 2019;33(6):e22913.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Uno M, Tsuji H, Watanabe M, Takada O, Kobayashi K, Takabuchi H, et al. Application of thrombin-antithrombin III complex for detecting a latent hypercoagulable state in patients with coronary artery disease. Jpn Cric J. 1989;53(10):1185–91.

    Article  CAS  Google Scholar 

  14. Song P, Xie J, Li W, Zhang X, Sun Z, You C. Effect of plasma thrombin-antithrombin complex on ischemic stroke: a systematic review and meta-analysis. Syst Rev. 2023;12(1):17.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Innocenti F, Gori AM, Giusti B, Tozzi C, Donnini C, Meo F, et al. Prognostic value of sepsis-induced coagulation abnormalities: an early assessment in the emergency department. Intern Emerg Med. 2019;14(3):459–66.

    Article  PubMed  Google Scholar 

  16. Mitusch R, Siemens HJ, Garbe M, Wagner T, Diederich KW. Detection of a hypercoagulable state in nonvalvular atrial fibrillation and the effect of anticoagulant therapy. Thromb Haemost. 1996;75(2):219–23.

    Article  CAS  PubMed  Google Scholar 

  17. Schaller J, Gerber SS. The plasmin-antiplasmin system: structural and functional aspects. Cell Mol Life Sci. 2011;68(5):785–801.

    Article  CAS  PubMed  Google Scholar 

  18. Asanuma K, Nakamura T, Hagi T, Okamoto T, Kita K, Nakamura K, et al. Significance of coagulation and fibrinolysis markers for benign and malignant soft tissue tumors. BMC Cancer. 2021;21(1):364.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Loghmani H, Conway EM. Exploring traditional and nontraditional roles for thrombomodulin. Blood. 2018;132(2):148–58.

    Article  CAS  PubMed  Google Scholar 

  20. Asakawa H, Tokunaga K, Kawakami F. Elevation of fibrinogen and thrombin- antithrombin III complex levels of type 2 diabetes mellitus patients with retinopathy and nephropathy. J Diabetes Complications. 2000;14(3):121–6.

    Article  CAS  PubMed  Google Scholar 

  21. Wei HJ, Li YH, Shi GY, Liu SL, Chang PC, Kuo CH, et al. Thrombomodulin domains attenuate atherosclerosis by inhibiting thrombin-induced endothelial cell activation. Cardiovasc Res. 2011;92(2):317–27.

    Article  CAS  PubMed  Google Scholar 

  22. Wada H, Minamikawa K, Wakita Y, Nakase T, Kaneko T, Ohiwa M, et al. Increased vascular endothelial cell markers in patients with disseminated intravascular coagulation. Am J Hematol. 1993;44(2):85–8.

    Article  CAS  PubMed  Google Scholar 

  23. Wyrzykowska P, Kasza A. Regulation of PAI-1 expression. Postepy Biochem. 2009;55(1):46–53.

    PubMed  Google Scholar 

  24. Chapin JC, Hajjar KA. Fibrinolysis and the control of blood coagulation. Blood Rev. 2015;29(1):17–24.

    Article  CAS  PubMed  Google Scholar 

  25. Zhou K, Zhang J, Zheng ZR, Zhou YZ, Zhou X, Wang LD et al. Diagnostic and prognostic value of TAT, PIC, TM, and t-PAIC in malignant tumor patients with venous thrombosis. Clin Appl Thromb Hemost. 2020; 1076029620971041.

  26. Horn PS, Pesce AJ. Reference intervals: an update. Clin Chim Acta. 2003;334(1–2):5–23.

    Article  CAS  PubMed  Google Scholar 

  27. Tagalakis V, Kahn S. The epidemiology of venous thromboembolism in the Elderly: a Population-based study. Blood. 2009;114(22):2980.

    Article  Google Scholar 

  28. Kawasaki T, Shinoki N, Iwamoto SI, Fujimura H, Yoshikawa N, Ohta Y, et al. Diagnostic value of plasma thrombin-antithrombin III complex and D-dimer concentration in patients with varicose veins for exclusion of deep-vein thrombosis. Thromb Res. 1998;91(2):101–4.

    Article  CAS  PubMed  Google Scholar 

  29. Rimpo K, Tanaka A, Ukai M, Ishikawa Y, Hirabayashi M, Shoyama T. Thrombin-antithrombin complex measurement using a point-of-care testing device for diagnosis of disseminated intravascular coagulation in dogs. PLoS ONE. 2018;13(10):e0205511.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Lin SM, Wang YM, Lin HC, Lee KY, Huang CD, Liu CY, et al. Serum thrombomodulin level relates to the clinical course of disseminated intravascular coagulation, multiorgan dysfunction syndrome, and mortality in patients with sepsis. Crit Care Med. 2008;36(3):683–9.

    Article  CAS  PubMed  Google Scholar 

  31. Öhlin AK, Larsson K, Hansson M. Soluble thrombomodulin activity and soluble thrombomodulin antigen in plasma. J Thromb Haemost. 2005;3(5):976–82.

    Article  PubMed  Google Scholar 

  32. Weiler H, Isermann BH, Thrombomodulin. J Thromb Haemost. 2003;1(7):1515–24.

    Article  CAS  PubMed  Google Scholar 

  33. Griffin JH, Zlokovic BV, Mosnier LO. Activated protein C, protease activated receptor 1, and neuroprotection. Blood. 2018;132(2):159–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Yasar Yildiz S, Kuru P, Toksoy Oner E, Agirbasli M. Functional stability of plasminogen activator inhibitor-1. Sci World J. 2014;2014:858293.

    Article  Google Scholar 

  35. Urano T, Castellino FJ, Suzuki Y. Regulation of plasminogen activation on cell surfaces and fibrin. J Thromb Haemost. 2018;16(8):1487–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Wu Y, Qiao Y, Zhang Y, Li Q, Zhang W. Trimester-specific reference intervals of TAT, TM, tPAI-C and PIC for healthy Chinese pregnant women. J Obstet Gynaecol Res. 2021;47(1):368–74.

    Article  CAS  PubMed  Google Scholar 

  37. Hayashi M, Inoue T, Hoshimoto K, Negishi H, Inaba N. Characterization of five marker levels of the hemostatic system and endothelial status in normotensive pregnancy and pre-eclampsia. Eur J Haematol. 2002;69(5–6):297–302.

    Article  CAS  PubMed  Google Scholar 

  38. Yang Y, Hu Y, Wu M, Xiang Z. Changes of new coagulation markers in healthy pregnant women and establishment of reference intervals in Changsha. J Cent South Univ Med Sci. 2022;47(4):469–78.

    Google Scholar 

  39. Khan M, shah SH, Salman M, Abdullah M, Hayat F, Akbar S. Enzyme-linked immunosorbent assayversuschemiluminescent immunoassay: a general overview. Glob J Med Pharm Biomed Update. 2023;18(1):1–5.

    Google Scholar 

  40. Chang L, Zhao JP, Guo F, Ji HM, Zhang L, Jiang XY, et al. Comparative evaluation and measure of Accuracy of ELISAs, CLIAs, and ECLIAs for the detection of HIV infection among blood donors in China. Can J Infect Dis Med Microbiol. 2020;2020:2164685.

    Article  PubMed  PubMed Central  Google Scholar 

  41. Douma RA, Tan M, Schutgens REG, Bates SM, Perrier A, Legnani C, et al. Using an age-dependent D-dimer cut-off value increases the number of older patients in whom deep vein thrombosis can be safely excluded. Haematologica. 2012;97(10):1507–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Han CW, Zhao YQ, Cheng WL, Yang J, Yuan J, Zheng YH, et al. The performance of age-adjusted D-dimer cut-off in Chinese outpatients with suspected venous thromboembolism. Thromb Res. 2015;136(4):739–43.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors thank Guangzhou Wondfo Biotech Co., Ltd. for providing technical assistance with the analyzer laboratory work. We would also like to thank Editage (www.editage.cn) for English language editing.

Funding

This study was financially supported by the National Key Research and Development Program (2022YFC2009600, 2022YFC2009602).

Author information

Authors and Affiliations

  1. Department of Clinical Laboratory, Beijing Anzhen Hospital, Capital Medical University, No.2 Anzhen Road, Beijing, China

    Lei Zhang, Hua Chen, Xu Peng & Hui Yuan

  2. Capital Medical University, Beijing, China

    Yiming Chen

  3. Health Examination Center, Beijing Anzhen Hospital, Capital Medical University, Beijing, China

    Rong Hu

Authors
  1. Lei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yiming Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Rong Hu
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hua Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Xu Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hui Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

All authors have accepted responsibility for the entire content of this manuscript and approved its submission. Lei Zhang performed the research and wrote the paper. Yiming Chen analyzed and organized the data. Rong Hu provided study materials. Hua Chen and Xu Peng collected and detected the samples. Hui Yuan provided administrative support and guided the research. All authors revised the text critically and agreed with the final contents.

Corresponding author

Correspondence to Hui Yuan.

Ethics declarations

Ethics approval and consent to participate

The authors state that all methods were carried out in accordance with relevant guidelines and regulations and followed the principles outlined in the Declaration of Helsinki for human. The study was approved by the Ethics Committee of Beijing Anzhen Hospital (KS2022006). Patient consent statements were obtained from all individuals included in this study.

Consent for publication

All authors agreed to publish this work.

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Zhang, L., Chen, Y., Hu, R. et al. A single-center study of reference intervals for TAT, PIC, TM and t-PAIC in healthy older Chinese adults. Thrombosis J 22, 82 (2024). https://doi.org/10.1186/s12959-024-00651-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1186/s12959-024-00651-2

Keywords

Thrombosis Journal

ISSN: 1477-9560

Contact us