Clinical efficacy of the Guanxinning tablet for stable angina pectoris in the elderly and its effects on molecular markers of the prethrombotic state / 中华老年医学杂志

Objective:To investigate the clinical efficacy of the Guanxinning tablet on the prethrombotic state in older adults with stable angina pectoris.Methods:In this study, 80 elderly patients with coronary heart disease and blood stasis admitted to our hospital between December 2019 and December 2021 were selected as the study subjects, and were randomly divided into a control group and an observation group(40 cases each). The control group was treated with Aspirin alone, and the observation group was treated with the Guanxinning tablet in addition to aspirin.Differences in traditional Chinese medicine(TCM)syndrome scores, weekly angina attacks and intervals between attacks, von Willebrand factor(vWF), thrombomodulin(TM), and granule membrane protein-140(GMP-140)levels between the two groups were compared.Results:There was no statistically significant difference in TCM syndrome scores between the observation group and the control group before treatment(11.34±2.2 vs.11.8±2.3, t=0.184, P=0.856), but there was a statistically significant difference between the observation group and the control group after treatment(6.5±1.8 vs.8.4±2.0 points, t=4.230, P=0.000). The number of weekly angina attacks and the interval between attacks in the observation group were significantly decreased compared with the control group, and the difference was statistically significant(all P<0.01). The levels of molecular markers of the prethrombotic state(vWF, TM and GMP-140)in the observation group were more favorable than those in the control group, with statistical significance(all P<0.05). Conclusions:The Guanxinning tablet can improve angina pectoris symptoms in elderly patients with coronary heart disease and effectively improve the expression of molecular markers of the prethrombotic state.

Predictive value of four items of new thrombus markers combined with conventional coagulation tests for thrombosis in antiphospholipid syndrome / 北京大学学报(医学版)

OBJECTIVE@#To explore the predictive value of four items of new thrombus markers combined with conventional coagulation tests for thrombosis in antiphospholipid syndrome.@*METHODS@#A total of 121 antiphospholipid syndrome (APS) patients who hospitalized at Peking University People's Hospital from March 2022 to January 2023 were selected and divided into thrombus group (50 cases) and nonthrombus group (71 cases) according to whether thrombosis occurred. The differences of laboratory characteristics including antiphospholipid antibodies were compared between the thrombotic and non-thrombotic groups. Chemiluminescent immunoassay was used to detect thrombomodulin (TM), thrombin-antithrombin complex (TAT), Plasmin-α2 plasmin inhibitor complex (PIC), and tissue plasminogen activator inhibitor complex (t-PAIC) in plasma from venous. The independent risk factors of thrombosis in patients with APS were determined using binary Logistic regression. Receiver operating characteristic (ROC) curve analysis was applied to evaluate the efficacy of each index on the prediction of thrombosis.@*RESULTS@#Compared with the patients without thrombosis, the patients with thrombosis were older [49 (32, 64) years vs. 36 (32, 39) years, P < 0.05]. The percentages of male, smoking, hypertension, and global antiphospholipid syndrome score (GAPSS)≥10 in the patients with thrombosis were significantly higher than those in the patients without thrombosis (P < 0.05). The positive rates of anticardiolipin antibody (aCL) and lupus anticoagulant (LA) in the thrombotic group were significantly higher than those in the non-thrombotic group (P < 0.05), and the levels of prothrombin time, activated partial thromboplastin time, fibrinogen, fibrin degradation product in the thrombotic group were significantly higher than those in the non-thrombotic group (P < 0.05).Among the thrombosis group, venous thrombosis accounted for 19 (38.00%), including deep vein thrombosis (16, 84.21%) and pulmonary embolism accounted (5, 26.32%); Arterial thrombosis accounted for 35 (70.00%), including myocardial infarction (6, 17.14%) cerebral infarction (30, 85.71%). The patients in the thrombotic group had significantly greater TM levels than those in the non-thrombotic group (P < 0.05).There were no significant dif-ferences between the two groups in TAT (Z=-1.420, P=0.156), PIC (Z=-0.064, P=0.949), and t-PAIC (Z=-1.487, P=0.137). Univariate and binary Logistic regression analysis of relevant variables showed that advanced age [OR=1.126, P=0.002], elevated TM [OR=1.325, P=0.048], prolonged prothrombin time (PT) [OR=4.127, P=0.008] were independent risk factors for thrombosis in the patients with APS. ROC curve analysis of the above three independent risk factors showed that the combined detection of age, PT and TM had the highest Yoden index (0.727) and sensitivity (83.0%), with a specificity of 89.7%.@*CONCLUSION@#TAT, PIC, TM, and t-PAIC may reflect thrombus formation from the coagulation system, fibrinolysis system, and endothelial system. The combined of age TM and PT is superior to the application of a single marker, which has diagnostic value for the early identification of APS thrombosis.

Research progress on therapeutic role of recombinant human soluble thrombomodulin in atherosclerosis / 中国临床药理学与治疗学

Atherosclerosis is a multifocal, smoldering, immunoinflammatory disease caused by lipid accumulation. Acute cardio-cerebrovascular disease caused by AS is one of the most serious life threats in the world. Endothelial cell injury, vascular inflammatory stimulation, abnormal lipid metabolism and coagulation disorder are the main pathological mechanisms of AS. Thrombomodulin (TM) is a transmembrane glycoprotein mainly expressed on the surface of endothelium. It plays a key role in maintaining the dynamic equilibrium of the vascular system through its functions of anti-coagulation, anti-inflammation and cell protection. Recombinant human soluble thrombomodulin (rhsTM), a soluble form of human TM containing the extracellular domain of TM, might be effective in the treatment of AS. This review summarizes the structure and function of TM and the mechanism of rhsTM in the treatment of AS. Aiming to provide new ideas for the prevention and treatment of AS.

Abnormal coagulation activity and the related clinical significance in patients with novel bunyavirus infection / 中华检验医学杂志

Objective:To explore the related indexes of coagulation and thrombosis and their clinical significance in patients with severe fever with thrombocytopenia symptoms (SFTS) during the onset and recovery period after novel bunyavirus infection.Methods:A total of 36 patients diagnosed with SFTS (SFTS onset group) and 18 convalescent SFTS patients, who were hospitalized in the First Affiliated Hospital of Anhui Medical University from April 12, 2020, to October 12, 2020 were recruited in this study. Thirty-six healthy controls were recruited from volunteers. Plasma was collected and prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time(TT), antithrombin-Ⅲ (AT-Ⅲ), fibrin degradation product (FDP) and D-dimer (D-D) were determined by automatic blood coagulation analyzer. Thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasminase-α2 plasminase inhibitor complex (PIC) and tissue plasminogen activator-plasminogen activator inhibitor 1 complex (t-PAIC) were determined by an automatic chemiluminescence analyzer.Results:Compared with the healthy control group, PT was significantly prolonged (12.5 [12.1, 13.6] s, vs 10.8 [10.5, 11.5] s, P<0.05) in SFTS onset group, but was still within the reference range (14.0-21.0 s), and APTT (49.1 [42.0, 58.2]s vs 28.5 [26.6, 30.4]s, P<0.05) was also significantly prolonged in SFTS onset group. Compared with healthy control group, FDP (6.07 [2.67, 8.64] μg/ml vs 1.00 [0.80, 1.87] μg/ml, P<0.001), D-D (2.27 [1.04, 2.98] μg/ml vs 0.30 [0.21, 0.47] μg/ml, P<0.001), TAT (16.05 [8.05, 26.58] ng/ml vs 3.55 [2.60, 4.85] ng/ml, P<0.001), PIC (4.44 [2.52, 5.54] μg/ml vs 0.84 [0.60, 1.35] μg/ml, P<0.001), TM ([19.41±8.29] TU/ml vs [9.33±1.89] TU/ml, P<0.001), and t-PAIC ([37.52±21.10] ng/ml vs [7.06±3.37] ng/ml, P<0.001) values were all significantly higher in the SFTS onset group (all P<0.001). The level of TAT in the SFTS recovery group (9.10 [3.95, 18.40] ng/ml) was still out of the reference range (<4 ng/ml), while the level of PIC in the SFTS recovery group was lower than in SFTS onset group (1.91 [1.45, 2.93] μg/ml vs 4.44 [2.52, 5.54] μg/ml, P<0.05). Compared with SFTS onset group, the levels of TM and t-PAIC were lower in the SFTS recovery group ( P<0.05). Conclusions:Coagulation system activation and vascular endothelial injury are evidenced in SFTS patients. In the convalescence period, the vascular endothelial injury is recovered, however, there is still a certain degree of coagulation dysfunction, therefore, it is necessary to monitor the coagulation indicator of discharged patients post SFTS.

Effect of urokinase on inflammatory substances and thrombomodulin in rats with deep vein thrombosis / 中国医师杂志

Objective:To investigate the mechanism of urokinase on inflammatory substances and thrombomodulin (TM) in deep vein thrombosis (DVT) rats.Methods:A rat model of deep vein thrombosis was established. Thirty rats were randomly divided into sham group, DVT group and UK (urokinase) group. The rat model of deep venous thrombosis was established in DVT group and UK group. One day after operation, urokinase (20 000 U/kg) was injected into caudal vein in UK group once a day for 14 days; Sham group and DVT group were given the same volume of normal saline. The wet weight and the ratio of wet weight/length of thrombus were compared among the three groups; HE staining was used to detect the pathological changes of thrombus in the three groups; The plasma inflammatory factors interleukin-8 (IL-8) and tumor necrosis factor α (TNF-α) were detected by enzyme-linked immunosorbent assay (ELISA). The mRNA expression of TM in the three groups was detected by real-time fluorescence quantitativepolymerase chain reaction (qRT-PCR).Results:Compared with sham group, thrombosis was found in DVT group. The wet weight and wet weight/length ratio of thrombus in DVT group were significantly higher than those in sham group ( P<0.05); After urokinase intervention, the wet weight of thrombus in UK group was significantly lower than that in DVT group, and the wet weight/length ratio of thrombus was also significantly lower than that in DVT group ( P<0.05). Compared with sham group, DVT group had obvious thrombosis, granulation tissue covered around the tissue, obvious adhesion between blood vessels and tube wall, a large number of inflammatory cell infiltration around venous tissue and obvious destruction of valve structure; After urokinase intervention, the thrombus tissue of UK group was significantly improved. Compared with sham group, the concentration of IL-8 , TNF-α and sTM in DVT group were significantly increased ( P<0.05). After urokinase intervention, the IL-8, TNF-α and sTM concentration in UK group were significantly lower than those in DVT group ( P<0.05). qRT-PCR results showed that TM mRNA expression in DVT group was significantly higher than that in sham group ( P<0.05). The TM mRNA expression in UK group was significantly lower than that in DVT group ( P<0.05). Conclusions:Urokinase can inhibit the inflammatory factors and the expression of thrombomodulin in DVT.

The predictive value of thrombomodulin for venous thromboembolism in patients with lung cancer / 中国医师进修杂志

Objective:To explore the predictive value of thrombomodulin (TM) for venous thromboembolism (VTE) in patients with lung cancer.Methods:The clinical data of 356 patients with lung cancer from March 2020 to March 2021 in Honghu People′s Hospital were retrospectively analyzed. Among them, 71 cases were diagnosed as VTE (VTE group) and 285 cases without VTE (non-VTE group). The D-Dimer (DD), fibrinogen degradation product (FDP), prothrombin time (PT), activated partial prothrombin time (APTT), thrombin time (TT) and TM were detected. Multivariate Logistic regression analysis was used to analyze the independent risk factors of VTE in patients with lung cancer, and the receiver operating characteristic (ROC) curve was used to analyze the predictive value of TM for VTE in patients with lung cancer.Results:There were no statistical differences in FDP, PT, APTT and TT between 2 groups ( P>0.05); the TM and DD in VTE group were significantly higher than those in non-VTE group: (11.61 ± 3.22) U/L vs. (7.70 ± 2.59) U/L and (5.42 ± 2.15) mg/L vs. (2.57 ± 0.96) mg/L, and there were statistical differences ( P<0.01). Multivariate Logistic regression analysis results showed that TM and DD were independent risk factors for VTE in patients with lung cancer ( OR = 0.27 and 0.66, 95% CI 0.19 to 0.39 and 0.56 to 0.78, P<0.01). ROC curve analysis result showed that the areas under curve of TM and DD for prediction VTE in patients with lung cancer were 0.830 and 0.892 (95% CI 0.772 to 0.889 and 0.842 to 0.941), and there was no statistical difference ( Z = 1.617, P>0.05); the optimum cut off values of TM and DD were 9.39 U/L and 3.83 mg/L, the sensitivity was 77.46% and 76.06%, and the specificity was 73.33% and 91.58%. Conclusions:The TM can be used as prediction index for VTE in patients with lung cancer.

Changes of new coagulation markers in healthy pregnant women and establishment of reference intervals in Changsha / 中南大学学报(医学版)

OBJECTIVES@#There is a high coagulation state in pregnant women, which is prone to coagulation and fibrinolysis system dysfunction. This study aims to explore the latest coagulation markers-thrombomodulin (TM), thrombin-antithrombin complex (TAT), plasmin-α2 plasmin inhibitor complex (PIC), and tissue plasminogen activator/plasminogen activator inhibitor compound (tPAI-C) in different stages of pregnancy, establish reference intervals (RIs) for healthy pregnant women of Chinese population, and to provide an effective and reliable reference for clinicians.@*METHODS@#A total of 492 healthy pregnant women, who underwent pregnancy examination and delivery in the Department of Obstetrics, Second Xiangya Hospital of Central South University from October 2019 to October 2020, were enrolled for this study. They were assigned into the first trimester group, the second trimester group, the third trimester group, and the puerperium group according to the pregnancy period, and 123 healthy non-pregnant women were selected as the controls. Plasma levels of TM, TAT, PIC and tPAI-C were analyzed by automatic chemiluminescence immunoassay analyzer. The RIs for TM, TAT, PIC, and tPAI-C were defined using non-parametric 95% intervals, determined following Clinical and Laboratory Standards Institute Document C28-A3c (CLSI C28-A3c), and Formulation of Reference Intervals for the Clinical Laboratory Test Items (WS/T402-2012).@*RESULTS@#TM and TAT levels increased gradually in the first, second, and third trimester women and decreased in the puerperium women (P<0.05 or P<0.01). PIC level of healthy non-pregnant women was lower than that of pregnant women (P<0.05 or P<0.01), but PIC level of pregnant and puerperium women did not differ significantly (P>0.05). tPAI-C level in healthy non-pregnant women was lower than that of pregnant women (P<0.05 or P<0.01), and tPAI-C level was significantly decreases in the puerperium women (P<0.01). The RIs for TM were as follows: Healthy non-pregnant women at 3.20-4.60 TU/mL, the first and second trimester at 3.12-7.90 TU/mL, the third trimester at 3.42-8.29 TU/mL, puerperium at 2.70-6.40 TU/mL. The RIs for TAT were as follows: Healthy non-pregnant women at 0.50-1.64 ng/mL, the first and second trimester at 0.52-6.91 ng/mL, the third trimester at 0.96-12.92 ng/mL, puerperium at 0.82-3.75 ng/mL. The RIs for PIC were as follows: Healthy non-pregnant women at 0.160-0.519 ng/mL, pregnant women at 0.162-0.770 μg/mL. The RIs for tPAI-C were as follows: Healthy non-pregnant women at 1.90-4.80 ng/mL, the first and second trimester at 2.03-9.33 ng/mL, the third trimester at 2.80-14.20 ng/mL, puerperium at 1.10-8.40 ng/mL.@*CONCLUSIONS@#The levels of 4 new coagulation markers TM, TAT, PIC, and tPAI-C in pregnant women are increased significantly during pregnancy and gradually return to normal after delivery. The RIs for TM, TAT, PIC, and tPAI-C in pregnant women by trimester are established according to CLSI C28-A3c, thus providing a clinical reference for clinician in judgement of thrombotic risk.

Detection and Clinical Significance of Thrombus Molecular Markers in Diffuse Large B-cell Lymphoma / 肿瘤防治研究

Objective To investigate the detection and clinical significance of thrombus molecular markers in diffuse large B-cell lymphoma (DLBCL). Methods We collected the blood specimens of 60 patients with DLBCL, involving 23 cases in the initial treatment group, 24 cases in the remission group and 13 cases in the non-remission group, 23 cases in the thrombus group and 37 cases in the non-thrombus group. We selected 46 healthy people in the same period as the control group. The levels of thrombomodulin (TM), plasmin-α2 plasmin inhibitor complex (PIC), tissue plasminogen activator-plasminogen activator inhibitor-1 complex (t-PAIC) and thrombin-antithrombin Ⅲ complex (TAT) in plasma were detected by chemical immunoassay, and the levels of lactate dehydrogenase (LDH) in serum was detected by automatic biochemical analyzer. We analyzed the differences of thrombus molecular markers among groups and prognostic factors. Results The levels of TM and PIC in plasma of lymphoma patients were higher than those in health control group (P < 0.05). The levels of TM and PIC in the initial treatment and non-remission groups were significantly higher than those in the remission group (P < 0.05). The levels of TM, PIC and TAT in thrombus group were higher than those in non-thrombus group (P < 0.05). TM and PIC levels in plasma were closely related to the prognosis of DLBCL patients. PIC was an independent prognostic factor (P < 0.001). TM and PIC levels were correlated with LDH prognostic indicators in lymphoma patients. Conclusion TM and PIC levels in plasma are significantly increased in DLBCL patients. They are expected to be the indicators for effectiveness and prognosis of DLBCL patients.

The Role of Thrombomodulin in Diseases / 中国生物化学与分子生物学报

Thrombomodulin (TM) is a single-chain transmembrane glycoprotein that mainly exists in vascular endothelial cells, hematopoietic progenitor cells, monocytes and macrophages. TM is mainly composed of five structural regions: the N-terminal lectin-like domain which plays a role in anti-inflammatory, and the six epidermal growth factor-like repeats which function as coagulation and fibrinolysis as well as serine-rich threonine regions and transmembrane domains and cytoplasmic domains. TM exhibits anti-inflammatory and anticoagulant effects by binding to thrombin to activate protein C, and TM-thrombin complex can also activate fibrinolytic inhibitors to suppress fibrinolysis. Previous reports showed that inhibiting epithelial mesenchymal transformation, mitogen-activated protein kinase or activating protein C and fibrinolytic inhibitor are the major mechanisms by which TM exerts anti-tumor properties. In atherosclerosis, TM can prevent atherosclerosis by blocking the activation of thrombin-mediated PAR-1 and inhibiting autophagy and apoptosis of endothelial cells. TM lectin-like domains can also bind to thrombin to inhibit its activity and further inhibit pulmonary thrombosis, fibrosis and inflammation. Moreover, TM protein is also involved in the pathogenesis of diabetic nephropathy, preeclampsia and ischemia-reperfu-sion injury. At present, TM is only clinically used for the treatment of sepsis and disseminated intravascular coagulation. Its role and therapeutic potential in cardiovascular and cerebrovascular diseases, cancers and other diseases deserve further exploration.

Epidermal growth factor receptor regulates fibrinolytic pathway elements in cervical cancer: functional and prognostic implications

Epidermal growth factor receptor (EGFR) signaling and components of the fibrinolytic system, including urokinase-type plasminogen activator (uPA) and thrombomodulin (TM), have been implicated in tumor progression. In the present study, we employed cBioPortal platform (http://www.cbioportal.org/), cancer cell lines, and an in vivo model of immunocompromised mice to evaluate a possible cooperation between EGFR signaling, uPA, and TM expression/function in the context of cervical cancer. cBioPortal analysis revealed that EGFR, uPA, and TM are positively correlated in tumor samples of cervical cancer patients, showing a negative prognostic impact. Aggressive human cervical cancer cells (CASKI) presented higher gene expression levels of EGFR, uPA, and TM compared to its less aggressive counterpart (C-33A cells). EGFR induces uPA expression in CASKI cells through both PI3K-Akt and MEK1/2-ERK1/2 downstream effectors, whereas TM expression induced by EGFR was dependent on PI3K/Akt signaling alone. uPA induced cell-morphology modifications and cell migration in an EGFR-dependent and -independent manner, respectively. Finally, treatment with cetuximab reduced in vivo CASKI xenografted-tumor growth in nude mice, and decreased intratumoral uPA expression, while TM expression was unaltered. In conclusion, we showed that EGFR signaling regulated expression of the fibrinolytic system component uPA in both in vitro and in vivo settings, while uPA also participated in cell-morphology modifications and migration in a human cervical cancer model.

Clinical value of thrombomodulin combined with thrombin-antithrombin complex for judging prognosis for sepsis / 解放军医学杂志

[Abstract] Objective To determine the prognostic value of thrombomodulin (TM) combined with thrombin-antithrombin complex (TAT) in patients with sepsis. Methods A retrospective analysis of the clinical data from 80 patients with sepsis who met the inclusion and exclusion criteria admitted to the 908th Hospital of Chinese PLA Logistical Support Force from May 2018 to July 2019. The conventional coagulation tests, thromboelastographic (TEG) parameters, TM, TAT, α2-plasmin inhibitor-plasmin complex (PIC, namely plasmin/alpha 2-antiplasmin complex, PAP) and tissue plasminogen activator-inhibitor-1 complex (t-PAIC) were collected within 2 hours at admission. According to the prognosis of 90 days, the patients were divided into survival group and death group and statistical analysis were performed. Results Compared with TM [11.7(8.8, 15.9) TU/ml] and TAT [11.3(7.0, 20.5) ng/ml] in the survival group, TM [20.2(14.1, 23.8) TU/ml] and TAT [17.7(11.8, 54.6) ng/ml] were significantly increased in the death group (P16.95 TU/ml combined with TAT>10.55 ng/ml. Conclusion TM combined with TAT can effectively judge the prognosis of sepsis patients and early identify sepsis related coagulation disorders.

The impact of glucocorticoid on coagulation of smoke inhalation induced lung injury / 中华急诊医学杂志

Objective To explore the impact of glucocorticoid on coagulation through administrating on rats with smoke inhalation.Methods Totally 150 male S-D rats were randomly (random number) divided into 5 groups:control group (ambient air inhalation),smoke group (smoke inhalation for 30 min),smoke+high dosage methyl prednisolone group(MP 40 mg/kg,intraperitoneal injection,s+HMP group),smoke+medium dosage MP (4 mg/kg) group (s+MMP group),smoke+low dosage MP (0.4 mg/kg) group (s+LMP group) (all n=30).Survival rates were calculated 24 h after smoke inhalation.Lung tissues were collected for histopathology and wet to dry (W/D) ratio.Arterial blood was collected for blood gas test.Coagulation factors in lung and plasma were tested.Results Survival rates of three MP groups were markedly improved compared with the smoke group (all P＜0.05),and was significantly higher in the medium dosage group(85.17％) than those in the low and high dosage groups (65.73％ and 60.07％,all P＜0.05).The W/D ratio and blood gas test were markedly improved in the high and medium groups (all P＜0.05).Tissue factor (TF) and thrombin-antithrombin complex (TAT-c) in bronchoalveolar lavage fluid (BALF) increased dramatically after SI (P＜0.01,P=0.005) with a remarkable drop of factor Ⅱ (F Ⅱ) (P=0.007),all of which were attenuated by MP with dosage dependence.The mRNA expression of TF increased dramatically after SI and recovered significantly with MP administration,while the expression of thrombomodulin (TM) recovered in the opposite direction with MP,all of which were in a dosage dependent manner.TF,fibrinogen (FIB),TAT-c increased significantly in plasma after smoke inhalation (P＜0.01,P=0.027,P=0.005).F Ⅷ ％ increased with MP administration and TF was raised by high dosage MP compared with the smoke group.FIB and TAT-c were decreased in all MP groups,which were significant higher in the high and middle dosage groups.The change of TM and endothelial cell protein C receptor (EPCR) in circulation were similar with FIB or TAT-c with or without MP.Protein C (PC％) and antithrombin (AT Ⅲ ％) dropped dramatically after SI,high and middle dosages of MP could restore the activity significantly,while low dosage would restore AT Ⅲ ％ but not PC％.Conclusions Glucocorticoid can significantly improve local and systemical coagulation disorder caused by smoke inhalation,and high-and medium-dosage hormones are effective.The regulation of hormones on the coagulation system is an important mechanism in the treatment of smoke inhalation induced lung injury.

A evaluation of coagulation biomarkers for diagnosis and therapeutic monitoring of deep venous thrombosis of lower extremities / 临床检验杂志

Objective@#To evaluate the changes of molecular markers of thrombosis in patients with deep venous thrombosis of lower extremities and analyze their value in the detection of venous thrombosis and evaluate the therapeutic effects. @*Methods@#In case-control study, we selected traumatic patients after surgery from Beijing Jishuitan Hospital during December 2018 to May 2019. A total of 64 patients with thrombosis were in DVT group, 39 patients without thrombosis were in non-DVT group, and 28 healthy subjects in the same period were in healthy control group. Venous blood samples were taken from all these people. Coagulation parameters thrombin-antithrombin complexes (TAT), plasmin-α2-plasmin inhibitor complexes (PIC) and tissue-type plasminogen activator-inhibitor complexes (t-PAIC) were detected at first diagnosis and one month after rivaroxaban anticoagulation therapy beginning. The differences of the markers between these groups were compared. @*Results@#The coagulation markers of the patients with lower extremity deep venous thrombosis increased significantly at diagnosis. The levels of plasma TAT, PIC, t-PAIC and sTM in DVT group were significantly higher than those in non-DVT group (P＜0.05). The levels of plasma TAT, PIC and t-PAIC in DVT group were higher than those in healthy control group (P＜0.05). There was no significant difference in sTM level between DVT group and healthy control group (P＞0.05). The results and changes of TAT, PIC, t-PAIC in the patients before and after one month of anticoagulation therapy were statistically different (P＜0.05) in comparison. @*Conclusion@#The molecular markers of thrombosis, TAT, PIC and t-PAIC, could effectively detect deep venous thrombosis of lower extremities and showed significant efficacy in evaluating the efficacy of anticoagulation therapy.

Application of four items of thrombosis detection in venous thrombosis of malignant tumor patients / 中国医师进修杂志

Objective@#To evaluate the clinical value of four items of thrombosis detection, including thrombin-antithrombin complex (TAT), α2-plasmin inhibitor-plasmin complex (PIC), thrombomodulin (TM) and tissue plasminogen activator-inhibitor complex (t-PAIC), combined with D-dimer (D-D) and fibrin degradation products (FDP) in venous thrombosis in patients with malignant tumor.@*Methods@#A total of 904 patients with malignant tumor from October 2017 to March 2019 in General Hospital of Heilongjiang Province Land Reclamation Bureau were selected (malignant tumor group), and 200 healthy physical examination patients were selected as healthy control group. Among 904 patients with malignant tumor, 92 patients had venous thrombosis (thrombosis group), and 812 patients had not venous thrombosis (non-thrombosis group). The TAT, PIC, TM, t-PAIC, FDP and D-D were detected. The relationship between TAT, PIC, TM, t-PAIC, D-D, FDP and venous thrombosis was analyzed by binary Logistic regression. The receiver operating characteristic (ROC) curve was used to determine the diagnostic performance of each index, and the maximum value of the Youden index was the optimal cut-off value.@*Results@#The TAT, PIC, TM, t-PAIC, D-D and FDP in malignant tumor group were significantly higher than those in healthy control group, and there were statistical differences (P<0.01). The TAT, PIC, TM, t-PAIC, D-D and FDP in thrombosis group were significantly higher than those in non-thrombosis group: 20.20 (12.30, 59.45) μg/L vs. 8.60 (4.87, 15.15) μg/L, 1.23 (0.69, 2.84) mg/L vs. 0.70 (0.37, 1.45) mg/L, 14.55 (8.12, 21.10) kU/L vs. 10.05 (7.975, 13.90) kU/L, 10.20 (7.30, 15.17) μg/L vs. 7.40 (5.20, 12.65) μg/L, 3.42 (1.38, 7.07) μg/L vs. 1.69 (0.53, 4.64) μg/L, 6.41 (3.21, 17.05) mg/L vs. 5.15 (2.26, 10.01) mg/L, and there were statistical differences (P<0.01 or <0.05). Binary Logistic regression analysis result showed that TAT, PIC, TM, t-PAIC, D-D and FDP were correlated with venous thrombosis in patients with malignant tumor (OR = 1.277, 1.209, 1.107, 1.089, 1.260, 1.078 and 0.002; P<0.01 or <0.05). ROC curve result showed that the optimal cut-off values of TAT, PIC, TM, t-PAIC, D-D and FDP in the diagnosis of venous thrombosis in patients with malignant tumor were 24.450 μg/L, 2.624 mg/L, 17.750 kU/L, 13.250 μg/L, 5.290 μg/L and 22.435 mg/L; and the area under curve (AUC) were 0.788, 0.659, 0.621, 0.597, 0.626 and 0.598, respectively. The AUC of TAT + PIC + TM + t-PAIC and TAT + PIC + TM + t-PAIC + D-D + FDP in the diagnosis of venous thrombosis in patients with malignant tumor were significantly higher than D-D + FDP (0.808 and 0.796 vs. 0.633). Ninety patients with TAT>24.450 μg/L or PIC>2.624 mg/L were selected. Fourty-five cases of them were injected with low molecular weight heparin (experimental group) for 6 weeks, and another 45 cases were not treated with low molecular weight heparin (control group). Both groups were followed up for 1 year. The incidence of venous thrombosis in the experimental group was significantly lower than that in control group: 2.22% (1/45) vs. 15.56% (7/45), the survival time was significantly longer than that in control group: (10.6 ± 3.1) months vs. (8.5 ± 2.8) months, and there were statistical differences (P<0.05), and no bleeding occurred in experimental group.@*Conclusions@#Four items of thrombosis detection combined with D-D and FDP is better than single detection. It is the best non-invasive method to detect venous thrombosis. It can predict the possibility of venous thrombosis in patients with malignant tumor at an early stage, and help patients actively use preventing drug, determine the best and most reasonable treatment time, improve the prognosis of patients, and prolong survival time.

Clinical study on the diagnostic value of thrombomodulin combined with thrombin-antithrombin complex in disseminated intravascular coagulation / 医学研究生学报

Objective According to the cell-based coagulation theory, antithrombin complex (TAT) reflecting the activation of coagulation system, plasmin-α2 anti-plasmin complex (PIC) reflecting the activation of fibrinolytic system, thrombomodulin (TM) and tissue plasminogen activator-plasminogen activator inhibitor-1 complex (t-PAIC) reflecting vascular endothelial function were selected to explore their diagnostic values for disseminated intravascular coagulation. Methods A prospective study was conducted on 154 patients in the Department of Critical Care Medicine of the 908th Hospital from May to December 2018. The subjects were divided into non-overt DIC group (n=134) and overt DIC group (n=20) according to the diagnostic criteria of International Thrombus and Hemostatic Association. The differences among groups of TM, t-PAIC, TAT and PIC were compared along with statistical analysis. Results Compared with TM [10.5 (8.0~14.3) TU/mL], TAT [9.6 (4.9~21.8) ng/mL], PIC [1.253 (0.789~2.802) μg/mL] and t-PAIC [ 11.2 (7.1~22.1) ng/mL] in non-overt DIC group, TM [16.8 (11.8~21.5) TU/mL], TAT [33.6 (10.3~120.0) ng/mL], PIC [4.080 (0.814~8.651) μg/mL] and t-PAIC [19.4 (10.0~30.1)ng/mL] ) in overt DIC group were significantly increased (P<0.05). The area under the curve of TM>14.85 TU/mL combined with TAT>23.05 ng/mL as the standard diagnostic overt DIC was 0.835 (P=0.000), and the sensitivity, specificity, positive predictive value and negative predictive value were 0.85, 0.761, 0.592, 0.925 respectively. Conclusion TM combined with TAT has a higher diagnostic efficacy for overt DIC.

Thrombomodulin and interleukin 6 as potential biomarkers of endothelial dysfunction and inflammation after renal transplant / Trombomodulina e interleucina 6 como potenciais biomarcadores da disfunção endotelial e da inflamação pós-transplante renal

ABSTRACT Introduction: Endothelial dysfunction may contribute to hypercoagulable and inflammation states presents in renal transplant, chronic kidney disease (CKD) and its causes. These disorders can be evaluated by markers, such as thrombomodulin (TM), von Willebrand factor (vWF) and interleukin 6 (IL-6). Objectives: The aim of this study was to assess TM, vWF and IL-6 in renal transplant recipients (RTR) and associate their plasma levels with primary cause of end-stage renal disease (ESRD) and allograft function. Methods: 160 RTR were grouped according to the primary cause of CKD (G1: glomerulopathy; G2: hypertensive nephrosclerosis; G3: diabetic nephropathy; and G4: other causes/unknown etiology); creatinine plasma levels (C1 < 1.4 and C2 ≥ 1.4 mg/dl); and the estimated glomerular filtration rate (eGFR) (R1< 60 and R2 ≥ 60 ml/min/1.73 m2). TM and vWF were determined by the enzyme-linked immunosorbent assay (ELISA) and IL-6 by flow cytometry. The results were presented as median, minimum and maximum; p-value < 0.05 was considered statistically significant. Results: TM levels were significantly higher in the G1 group compared to the others (G1: 8.38; G2: 5.51; G3: 5.88; G4: 6.33 ng/ml, p < 0.0001), and in the R1 group compared to R2 (R1: 6.65; R2: 6.19 ng/ml, p = 0.02). The concentration of IL-6, measured by the mean fluorescence intensity, was higher in C2 group when compared to C1 (C1: 7.9; C2: 13.35, p = 0.03). There was no difference in vWF levels among groups. TM correlated positively with IL-6 and creatinine, and negatively with eGFR. IL-6 also correlated positively with vWF. Conclusion: TM and IL-6 can be identified as potential markers for evaluating renal graft function. TM was more related to the primary cause of CKD compared to vWF and IL-6.

RESUMO Introdução: A disfunção endotelial pode contribuir para estados de hipercoagulabilidade e inflamação presentes no transplante renal e na doença renal crônica (DRC) e suas causas, podendo ser avaliada por marcadores como trombomodulina (TM), fator de von Willebrand (FvW) e interleucina 6 (IL-6). Objetivos: Avaliar TM, FvW e IL-6 em receptores do transplante renal (RTR) e associar seus níveis com a causa primária de DRC pré-transplante e função do enxerto. Métodos: Foram alocados 160 RTR em grupos de acordo com a causa primária da DRC (G1: glomerulopatias; G2: nefroesclerose hipertensiva; G3: nefropatia diabética; e G4: outras causas/etiologia desconhecida), os níveis plasmáticos de creatinina (C1 < 1.4 e C2 ≥ 1.4 mg/dl) e o ritmo de filtração glomerular estimado (eRFG) (R1< 60 e R2 ≥ 60 ml/min/1.73 m2). A TM e o FvW foram determinados pelo ensaio de imunoabsorção enzimática (ELISA) e a IL-6, por citometria de fluxo. Os resultados foram apresentados como mediana, mínimo e máximo; p < 0,05 foi considerado significativo. Resultados: Níveis de TM foram significativamente maiores no grupo G1 em comparação com os demais (G1: 8,38; G2: 5,51; G3: 5,88; G4: 6,33 ng/ml, p < 0,0001), e no grupo R1 comparado com o R2 (R1: 6,65; R2: 6,19 ng/ml, p = 0,02). A concentração de IL-6, avaliada pela intensidade média de fluorescência, foi maior no grupo C2 quando comparada com o C1 (C1: 7,9; C2: 13,35, p = 0,03). Não houve diferença entre os grupos para o FvW. TM correlacionou-se positivamente com IL-6 e creatinina e negativamente com eRFG. A IL-6 foi positivamente correlacionada com o FvW. Conclusão: TM e IL-6 podem ser apontadas como potenciais marcadores para avaliar a função do enxerto renal. A TM relacionou-se mais com a causa primária da DRC, se comparada com FvW e IL-6.

The significance of combined detection of P-selectin, TM and vWF in early prediction of severe acute pancreatitis / 中华内分泌外科杂志

Objective To investigate the value of P-selectin,thrombomodulin (TM) and von Willebrand factor (vWF) in identifying severe acute pancreatitis (SAP) at an early stage of the disease.Methods 80 patients with acute pancreatitis (25 mild,30 moderate and 25 severe) were selected in this study when they were admitted within 24 hours of the onset of symptoms.20 healthy volunteers were collected as the healthy control.Enzyme-linked immunosorbent assay (ELISA) was used to determine the levels of vascular endothelial cell damage markers (P-selectin,TM and vWF) in SAP patients and the control group.Results The levels of 3 markers were significantly higher in SAP patients than in the mild and moderate acute pancreatitis patients and healthy volunteers (P＜0.05).P-selectin,TM and vWF were independent markers for the development of SAP and had higher discriminative powers than conventional marker tumor necrosis factor(TNF-α)(P＜0.05).They were similar to the APACHE-Ⅱ scoring system in distinguishing SAP at an early stage.Conclusions P-selectin,TM and vWF are independent markers to identify the development of SAP at an early stage.They are obviously superior to TNF-α and similar to the APACHE-Ⅱ scoring system.

A clinical study of sepsis-related coagulation disorder / 中华急诊医学杂志

Objective To study in the correlation of the laboratory markers of coagulation,fibrinolysis and thrombosis in patients with sepsis and SOFA score,the procalcitonin (PCT) concentration and seven-day survival rate.Methods From February 2017 to March 2018,119 patients with sepsis admitted in ICU and another 119 patients with non-sepsis undergoing selective surgery were enrolled as control in this study.APTT (activated partial thromboplastin time),PT-INR (prothrombin time-international normalized ratio),FIB (fibrinogen),AT-Ⅲ (antithrombin Ⅲ),D-Dimer,FDP (fibrinogen degradation products),sTM (soluble thrombomodulin),TAT (thrombin antithrombin complex),PIC (plasmin-a2 plasminogen inhibitor complex) and t-PAI-C (tissue plasminogen activator and its inhibitor complex),were simultaneously monitored at admission.The correlation between the given laboratory markers mentioned and SOFA score,the PCT concentration and seven-day survival rate were analyzed with the Spearman correlation analysis.Results (① In the patients with sepsis,a positive correlation between SOFA score and sTM,t-PAI-C,TAT respectively was found,and a negative correlation between SOFA score and PLT (platelet count) was observed,and no correlation between SOFA score and PIC was noticed.(②) A positive correlation between PCT and sTM,t-PAI-C respectively was significant,a negative correlation between PCT and PLT was marked,and no correlation between PCT and AT-Ⅲ,TAT,PIC respectively was found.(③) A negative correlation between seven-day survival rate and sTM,t-PAI-C and TAT respectively was obvious,a positive correlation between seven-day survival rate and AT-Ⅲ,PLT respectively was occurred,and no correlation between seven-day survival rate and PIC was determined.Conclusions Soluble thrombomodulin (sTM),thrombin-antithrombin (TAT),antithrombin Ⅲ (AT-Ⅲ) and tissue plasminogen activator inhibitor complex (t-PAI-c) were good clinical monitoring indicators of coagulation disorder in patients with sepsis,which were the representative of the endothelial cell damage with highly activated coagulation,relatively insufficient anti-coagulation function and poor fibrin degradation ability.These were good adjuvants to PLT,INR and APTT for core diagnostic criteria of coagulation disorder in sepsis.

Analysis of Changes in Plasma Endothelial Protein C Receptor and Thrombomodulin Level in Patients with Joint Replacement During Perioperative Period / 现代检验医学杂志

Objective To evaluate the level of plasma endothelial cell protein C receptor (EPCR) and thrombomodulin (TM)in the perioperative period of artificial joint replacement.Methods 119 patients (male 32,female 87,age distribution 57.75 ±12.04) who underwent total knee replacement and total hip arthroplasty from March to June 2015 in Department of Orthopedics of Beijing Jishuitan Hospital were selected.The levels of plasma endothelial cell EPCR and TM were compared be fore and after operation for 1 and 3 days.Results ①The concentration of plasma EPCR on the first day after surgery was reduced by 40.34％ compared with preoperative,and on the third day after surgery reduced by 49.45％ compared with pre operative,and on the third day after surgery was reduced by 15.26％ compared with the first day after surgery.The differences were all statistically significant (F=5.63,P＜0.05).②The concentration of plasma TM on the first day after surgery was reduced by 12.77％ compared with preoperative,and on the third day after surgery reduced by 40.53％ compared with preoperative,and on the third day after surgery was reduced by 31.83％ compared with the first day after surgery.The differences were all statistically significant (F=7.87,P＜0.05).Conclusion The concentration of EPCR and TM were pro gressively reduced within 3 days after arthroplasty.

Change and clinical value of thrombomodulin in children with severe pneumonia / 国际检验医学杂志

Objective To study the change and clinical value of thrombomodulin (TM ) in children with se-vere pneumonia .Methods Sixty-five children cases of severe pneumonia were divided into the disseminated in-travascular coagulation (DIC) group and non-DIC group according to whether complicating DIC .And 30 healthy children were selected as the control group .Plasma TM levels were analysed and compared among the three groups .The receiver operating characteristic(ROC) curve was used to conduct the evaluation .Results The plasma TM level had statistically significant difference among the control group ,non-DIC group and DIC group(H=53 .14 ,P=0 .000) ,moreover the pairwise comparison also had statistical difference (P<0 .05) .A-mong sputum culture positive 24 cases of severe pneumonia complicating DIC ,the T M level had no statistical difference between the children patients with Gram-positive bacterial infection and children patients with Gram-negative bacterial infection(P>0 .05) .The area under ROC curve of TM for diagnosing DIC was 0 .74 . The sensitivity ,specificity ,positive likelihood ratio and negative likelihood ratio were 0 .76 ,0 .63 ,2 .05 and 0 .38 respectively .Conclusion The change of plasma TM level is associated with the severity of children with severe pneumonia ,and T M can be used as one of the reference indicators for the early diagnosis in children with severe pneumonia complicating DIC .