Age-Related Reference Values of Molecular Markers in Endothelial Cell Activation, Coagulation and Fibrinolysis in Thai Children Versus Adults.

Abstract Introduction: The hemostatic system is a developing and changing process relative to age. Although advances in the knowledge of hemostatic mechanisms have led to the development of new methods for measuring peptides or enzyme-inhibitor complexes, there are very limited data concerning normal reference values for these in children. Objectives: The aim of this study is to distinguish the difference(s) in various endothelial cell activation and hemostatic parameters between children and adults, and to establish the normal range of these parameters in normal children in different age groups. Materials and Methods: Blood was obtained from 96 normal Thai children and adults whose screening coagulation tests were normal. All children were categorized into 3 age groups: 1–5 yrs, 6–10 yrs, and 11–18 yrs. Endothelial cell activation parameters: von Willebrand Factor Antigen and Activity (VWF:Ag and VWF:Ac) and soluble thrombomodulin (sTM); coagulation parameters: activated Factor VII (FVIIa:C), tissue factor (TF), and Thrombin-Antithrombin Complex (TAT); and fibrinolytic parameters: tissue plasminogen activator (t-PA), plasminogen activator inhibitor (PAI-1), D-dimer, thrombin activatable fibrinolysis inhibitor (TAFIa) and Protein C activity (PC:Ac) were measured. Tests Children’s Age Range Adults (Mean ± SD) 1–5 yr (n=19) 6–10 yr (n=26) 11–18 yr (n=25) (n=25) ANOVA *p ≤ 0.05 compared with adults; **p ≤ 0.001 compared with adults VWF:Ag (%) 93.3 ± 25.7 110.3 ± 27.1 98.4 ± 31.0 100.5 ± 25.2 VWF:Ac (%) 72.1 ± 18.9 91.1 ± 20.6 82.0 ± 24.2 84.7 ± 21.8 sTM (ng/mL) 3.9 ± 1.6** 3.1 ± 0.9 3.1 ± 1.3 2.4 ± 1.1 Fibrinogen (mg/dL) 360.7 ± 56.9 384.4 ± 78.9 410.1 ± 109.4 360.7 ± 51.0 FVIIa:C (%) 68.0 ± 23.8 69.9 ± 23.1 75.0 ± 22.9 75.6 ± 19.7 TF (pg/mL) 218.8 ± 57.8** 152.7 ± 38.2 144.5 ± 46.7 126.6 ± 42.2 TAT (ug/L) 4.5 ± 3.3 2.2 ± 0.7 2.4 ± 1.2 3.7 ± 4.9 t-PA (ng/mL) 1.32 ± 0.56 1.19 ± 0.48 1.16 ± 0.28 1.27 ± 0.32 PAI-1 (ng/mL) 22.8 ± 13.2 29.4 ± 14.2* 27.3 ± 18.3 18.8 ± 11.9 D-dimer (mg/L) 0.52 ± 0.42* 0.44 ± 0.46 0.28 ± 0.33 0.21 ± 0.09 TAFIa μg/mL) ( 40.6 ± 9.7 44.4 ± 6.9 46.1 ± 6.1 42.2 ± 5.7 Protein C:Ac (%) 87.2 ± 18.3* 101.7 ± 15.6 101.1 ± 22.5 102.4 ± 17.4 As seen in the Table, children in all age groups showed no significant difference in mean levels of VWF:Ag and Ac, fibrinogen, FVIIa:C, TAT, t-PA and TAFIa compared to adults. However, compared to adults, children aged 1–5 had significantly higher mean values of sTM (p=0.001), TF (p=< 0.001), and D-dimer (p = 0.015) whereas they had significantly lower mean levels of PC:Ac (p=0.023). The mean levels of PAI-1 in children of all groups were high, especially in children in the 6–10 yr age group (p = 0.032). These data indicate a physiologic difference in endothelial cell activation and hemostatic system between children and adults. Our data will serve as a useful reference guide in interpreting test results from children with suspected bleeding disorders.

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Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways

Blood ◽

10.1182/blood.v76.12.2520.2520 ◽

1990 ◽

Vol 76 (12) ◽

pp. 2520-2526 ◽

Cited By ~ 543

Author(s):

SJ van Deventer ◽

HR Buller ◽

JW ten Cate ◽

LA Aarden ◽

CE Hack ◽

...

Keyword(s):

Endothelial Cell ◽

Plasminogen Activator ◽

Cell Activation ◽

Plasminogen Activator Inhibitor ◽

Contact System ◽

Initial Increase ◽

Cytokine Release ◽

Endothelial Cell Activation ◽

System A ◽

Von Willebrand

Abstract Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.

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Hemostatic system changes predictive value in patients with ischemic brain disorders

Vojnosanitetski pregled ◽

10.2298/vsp0204377r ◽

2002 ◽

Vol 59 (4) ◽

pp. 377-384 ◽

Cited By ~ 2

Author(s):

Ranko Raicevic ◽

Aco Jovicic ◽

Slavka Mandic-Radic ◽

Dragana Djordjevic ◽

Bratislav Magdic ◽

...

Keyword(s):

Predictive Value ◽

Antithrombin Iii ◽

Degradation Products ◽

Protein S ◽

Factor Vii ◽

Brain Disorders ◽

Ischemic Brain ◽

Hemostatic System ◽

Pai 1 ◽

D Dimer

The aim of this research was to determine the importance of tracking the dynamics of changes of the hemostatic system factors (aggregation of thrombocytes, D-dimer, PAI-1, antithrombin III, protein C and protein S, factor VII and factor VIII, fibrin degradation products, euglobulin test and the activated partial thromboplastin time ? aPTPV) in relation to the level of the severity of ischemic brain disorders (IBD) and the level of neurological and functional deficiency in the beginning of IBD manifestation from 7 to 10 days, 19 to 21 day, and after 3 to 6 months. The research results confirmed significant predictive value of changes of hemostatic system with the predomination of procoagulant factors, together with the insufficiency of fibrinolysis. Concerning the IBD severity and it's outcome, the significant predictive value was shown in the higher levels of PAI-1 and the lower level of antithrombin III, and borderline significant value was shown in the accelerated aggregation of thrombocytes and the increased concentration of D-dimer. It could be concluded that the tracking of the dynamics of changes in parameters of hemostatic system proved to be an easily accessible method with the significant predictive value regarding the development of more severe. IBD cases and the outcome of the disease itself.

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Activation of endothelial cells, coagulation and fibrinolysis in children with Dengue virus infection

Thrombosis and Haemostasis ◽

10.1160/th06-02-0094 ◽

2007 ◽

Vol 97 (04) ◽

pp. 627-634 ◽

Cited By ~ 68

Author(s):

Panya Seksarn ◽

Sureeporn Pongsewalak ◽

Usa Thisyakorn ◽

Jeanne Lusher ◽

Darintr Sosothikul

Keyword(s):

Endothelial Cells ◽

Endothelial Cell ◽

Dengue Virus ◽

Plasminogen Activator ◽

Cell Activation ◽

Cell Injury ◽

Clinical Severity ◽

Coagulation Cascade ◽

Severe Bleeding ◽

Pai 1

SummaryDengue virus causes a febrile illness: Dengue fever (DF), and less frequently a life-threatening illness: Dengue hemorrhagic fever (DHF). Although severe bleeding remains a major cause of death in DHF, the pathogenesis of bleeding is poorly understood. This prospective cohort study was designed to determine the extent of activation of endothelial cells and the hemostatic system in correlation with clinical severity, and also to detect the best prognostic factor(s) for DHF. Endothelial cell activation, coagulation, anticoagulant and fibrinolysis parameters were measured in 42 children with Dengue infections (20 with DF and 22 with DHF) during three phases of illness. In DHF patients, during the febrile phase, vonWillebrand factor antigen (vWF:Ag),tissue factor (TF) and plasminogen activator inhibitor (PAI-1) were significantly elevated, while platelet counts andADAMTS 13 (a disintegrin and metalloprotease with thrombospondin repeats) were significantly low compared to DF patients. During the toxic phase, soluble thrombomodulin (sTM), tissue plasminogen activator (t-PA) and PAI-1 were also significantly increased, while ADAMTS 13 and thrombin activatable fibrinolysis inhibitor (TAFIa) were significantly low compared to DF patients. Abnormal vWF multimers were seen only in DHF patients. For endothelial cell injury and release of procoagulant components, activation of the coagulation cascade with thrombin generation, increased antifibrinolytic factors and consumption of natural anticoagulants, each appeared to play an important role in the development of hemorrhage in Dengue patients. Using logistic regression analysis, we found plasma VWF:Ag to be the best indicator of progression to DHF.

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Experimental endotoxemia in humans: analysis of cytokine release and coagulation, fibrinolytic, and complement pathways

Blood ◽

10.1182/blood.v76.12.2520.bloodjournal76122520 ◽

1990 ◽

Vol 76 (12) ◽

pp. 2520-2526 ◽

Cited By ~ 8

Author(s):

SJ van Deventer ◽

HR Buller ◽

JW ten Cate ◽

LA Aarden ◽

CE Hack ◽

...

Keyword(s):

Endothelial Cell ◽

Plasminogen Activator ◽

Cell Activation ◽

Plasminogen Activator Inhibitor ◽

Contact System ◽

Initial Increase ◽

Cytokine Release ◽

Endothelial Cell Activation ◽

System A ◽

Von Willebrand

Endotoxemia was evoked by bolus injection of Escherichia coli endotoxin (2 ng/kg body weight) in six healthy subjects to investigate the early kinetics of cytokine release in relation to the development of clinical and hematologic abnormalities frequently seen in gram-negative septicemia. The plasma concentration of tumor necrosis factor (TNF) increased markedly after 30 to 45 minutes, and reached a maximal level after 60 to 90 minutes. In each volunteer, the initial increase of plasma interleukin 6 (IL-6) concentrations occurred 15 minutes after the initial TNF increase, and maximal IL-6 concentrations were reached at 120 to 150 minutes. A transient increase in body temperature and pulse rate occurred simultaneously with the initial TNF and IL-6 increases, whereas a significant decrease in blood pressure occurred after 120 minutes. These changes were proportional to the changes in TNF and IL-6 concentrations. Coagulation activation, as assessed by a rise of prothrombin fragments and thrombin-antithrombin III complexes, was noted after 120 minutes, in the absence of activation of the contact system. A two- to sixfold increase in the concentrations of tissue plasminogen activator (t-PA) and von Willebrand factor antigen indicated endothelial cell activation. This increase started at 120 and 90 minutes, respectively. The release of t-PA coincided with activation of the fibrinolytic pathway, as measured by plasmin-alpha 2-antiplasmin complexes. The fibrinolytic activity of t-PA was subsequently offset by release of plasminogen activator inhibitor, observed 150 minutes after the endotoxin injection, and reaching a peak at 240 minutes. No complement activation was detected. These results show that in humans endotoxin induces an early, rapidly counteracted fibrinolytic response, and a more long-lasting activation of thrombin by a mechanism other than contact system activation. In addition, our data suggest that endotoxin-induced leukopenia and endothelial cell activation are mediated by TNF.

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The Compass-COVID19-ICU Study: Identification of Factors to Predict the Risk of Intubation and Mortality in Patients with Severe COVID-19

Blood ◽

10.1182/blood-2021-146483 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 2121-2121

Author(s):

Patrick Van Dreden ◽

Douglas D Fraser ◽

Guillaume Voiriot ◽

Aurélie Rousseau ◽

Ismail Elalamy ◽

...

Keyword(s):

Endothelial Cell ◽

Research Funding ◽

Cell Activation ◽

Prognostic Score ◽

Unmet Need ◽

High Sensitivity ◽

Protein S ◽

Clinical Predictors ◽

Endothelial Cell Activation ◽

D Dimer

Abstract Background: In some patients, SARS-CoV-2 infection induces cytokine storm, hypercoagulability and endothelial cell activation leading to worsening of COVID-19, intubation and death. Prompt identification of patients at risk of intubation or death is un unmet need. Objective: To derive a prognostic score for the risk of intubation or death in patients with critical COVID-19 by assessing biomarkers of hypercoagulability, endothelial cell activation and inflammation and a large panel of clinical analytes. Methods: We conducted a prospective, observational monocentric study enrolling 118 patients with COVID-19 admitted in the intensive care unit. At the 1st day of ICU admission all patients were assessed for the following biomarkers : protein C, protein S, antithrombin, D-Dimer, fibrin monomers, factors VIIa, V, XII, XII, VIII, von Willebrand antigen, fibrinogen, procoagulant phospholipid dependent clotting time, TFPI, thrombomodulin, P-selectin, heparinase, microparticles exposing tissue factor, IL-6, complement C3a, C5a, thrombin generation, prothrombin time, activated partial thromboplastin time, hemogram, platelet count) and clinical predictors. The clinical outcomes were intubation and mortality during hospitalization in ICU. Results: The intubation and mortality rate were 70 % and 18% respectively. Multivariate analysis led to the derivation of the COMPASS- COVID19-ICU score composed of P-Selectin, D-Dimer, free TFPI, TF activity, IL-6 and FXII, age and duration of hospitalization. The score predicted the risk of intubation or death with high sensitivity and specificity (0.90 and 0.92, respectively). Conclusions and Relevance: Critical COVID-19 is related with severe endothelial cell activation and hypercoagulability orchestrated in the context of inflammation. The COMPASS-COVID19-ICU score is an accurate predictive model for the evaluation of the risk of mechanical ventilation and death in patients with critical COVID-19. The assessment with the COMPASS- COVID-19-ICU score is feasible in tertiary hospitals. In this context it could be placed in the diagnostic procedure of personalized medical management and prompt therapeutic intervention. Disclosures Terpos: Novartis: Honoraria; Janssen: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding. Dimopoulos: Amgen: Honoraria; BMS: Honoraria; Takeda: Honoraria; Beigene: Honoraria; Janssen: Honoraria.

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Inhibition of coagulation, fibrinolysis, and endothelial cell activation by a p38 mitogen-activated protein kinase inhibitor during human endotoxemia

Blood ◽

10.1182/blood-2002-11-3338 ◽

2003 ◽

Vol 101 (11) ◽

pp. 4446-4448 ◽

Cited By ~ 51

Author(s):

Judith Branger ◽

Bernt van den Blink ◽

Sebastiaan Weijer ◽

Abhya Gupta ◽

Sander J.H. van Deventer ◽

...

Keyword(s):

Endothelial Cell ◽

Protein Kinase ◽

Plasminogen Activator ◽

P38 Mapk ◽

Cell Activation ◽

Plasma Concentrations ◽

Mitogen Activated Protein Kinase ◽

Tissue Type ◽

Endothelial Cell Activation ◽

Mitogen Activated Protein

Abstract P38 mitogen-activated protein kinase (MAPK) is an important component of intracellular signaling cascades that initiate various inflammatory cellular responses. To determine the role of p38 MAPK in the procoagulant response to lipopolysaccharide (LPS), 24 healthy subjects were exposed to an intravenous dose of LPS (4 ng/kg), preceded 3 hours earlier by orally administered 600 or 50 mg BIRB 796 BS (a specific p38 MAPK inhibitor), or placebo. The 600-mg dose of BIRB 796 BS strongly inhibited LPS-induced coagulation activation, as measured by plasma concentrations of the prothrombin fragment F1 + 2. BIRB 796 BS also dose dependently attenuated the activation and subsequent inhibition of the fibrinolytic system (plasma tissue-type plasminogen activator, plasmin-α2-antiplasmin complexes, and plasminogen activator inhibitor type 1) and endothelial cell activation (plasma soluble E-selectin and von Willebrand factor). Activation of p38 MAPK plays an important role in the procoagulant and endothelial cell response after in vivo exposure to LPS.

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Influence of insulin-induced hypoglycemia on the hemostatic and fibrinolytic system in patients with hypothalamicpituitary disorders

Hämostaseologie ◽

10.1055/s-0038-1655335 ◽

1998 ◽

Vol 18 (02) ◽

pp. 74-79

Author(s):

K.-H. Zurborn ◽

H. D. Bruhn ◽

H. Mönig

Keyword(s):

Factor Viii ◽

Plasminogen Activator ◽

Tolerance Test ◽

Insulin Tolerance Test ◽

Fibrinolytic System ◽

Tissue Type ◽

Insulin Tolerance ◽

Factor Viii Antigen ◽

Pai 1 ◽

D Dimer

SummaryIn order to study the acute and prolonged effects of hypoglycemia on the hemostatic and fibrinolytic system we measured prothrombin fragment (F1+2), thrombin-antithrombin III complex (TAT), platelet factor 4 (PF4), β-thromboglobulin (âTG), factor VIII antigen (F VIII antigen), D-dimer, tissue-type plasminogen activator (t-PA) antigen, and plasminogen activator inhibitor (PAI-1) in 22 patients during insulin tolerance test. F1+2 and TAT increased significantly 15 and 90 minutes after administration of insulin, as did PF4 and âTG. At 4 and 24 hours, these parameters were not different from baseline. Factor VIII antigen was not significantly altered. D-dimer concentration did not change. However, the D-dimer/TAT ratio significantly decreased at 15 and 90 minutes but increased markedly above baseline at 4 and 24 hours. t-PA antigen was also found to be elevated at 15 and 90 minutes but had returned to baseline at 4 and 24 hours. PAI-1 concentration did not change. We conclude from these data that both coagulation and fibrinolysis are activated in the short-term response to acute insulin-induced hypoglycemia, followed by a prolonged activation of fibrinolysis. Our study may explain why patients undergoing insulin tolerance test, despite marked clotting and platelet activation, almost never develop thromboembolic complications.

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