Relationship of Markers of Inflammation, Infection and Endothelial Function to Mortality and Severity of Coagulopathy in Patients with Sepsis-Associated DIC

Abstract Background: Sepsis-associated disseminated intravascular coagulation (DIC) is a complex clinical scenario involving derangement of many processes, including hemostasis. Assessment of markers of these other aspects of disease, including inflammation, immunity, endothelial function, and endogenous anticoagulants may provide insight into DIC pathophysiology and lead to improved methods for assessment of patient condition and response to treatment. This study was designed to measure biomarkers representative of multiple systems involved in DIC development in a cohort of patients with sepsis and DIC and determine the association of these biomarkers with disease severity and mortality. Materials and Methods: Citrated plasma samples were prospectively collected from 102 patients with sepsis and suspected DIC at ICU admission (day 0) and again serially on ICU days 4 and 8 under an IRB approved protocol. DIC score was determined using the ISTH scoring algorithm (e.g. platelet count, PT/INR, fibrinogen, and D-Dimer). Plasma from healthy individuals was purchased from a commercial laboratory (George King Biomedical, Overland, KS). . CD 40 Ligand (CD40L), Plasminogen inhibitor 1 ( PAI-1), nucleosomes, Procalcitonun (PCT), Microparicle Tissue Factor (MP-TF), and Prothrombin Fragment 1.2 (F1.2) were measured using commercially available ELISA kits. Protein C activity was measured using a clot-based assay. Interleukin 6 (IL-6), Interleukin 8 (IL-8), Interleukin 10 (IL-10) , Tumor Necrosis Factor Alpha (TNFα) , Monocyte Chemoattractant protein 1 (MCP-1) were measured using a biochip technology. Results: Significant differences in levels of Protein C (p=0.009), PCT (p=0.0005), IL-6 (p=0.019), IL-8 (p= 0.015), and PAI-1 (p=0.015) were observed between survivors and non-survivors (Table 1). Significant variation of Protein C (p=0.002), nucleosomes (p=0.05), PCT (P<0.001), IL-6 (p=0.001), IL-8 (p=0.003), IL-10 (p=0.011), TNFα (p=0.021), and MCP-1 (p=0.21), were observed based on severity of DIC score. Conclusion: Markers from multiple systems perturbed in DIC were associated with mortality suggesting that while these systems may not be routinely evaluated in the course of patient care, dysfunction of these system contribute significantly to mortality. In addition, numerous inflammatory cytokines showed an association with DIC score. This study suggests that the measurement of additional markers in sepsis-associated DIC may be of value in the prediction of mortality and may be helpful in guiding treatment for these patients. Disclosures No relevant conflicts of interest to declare.

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Immunological Determinants of Clinical Outcome in Peruvian Patients with Tegumentary Leishmaniasis Treated with Pentavalent Antimonials

Infection and Immunity ◽

10.1128/iai.01513-08 ◽

2009 ◽

Vol 77 (5) ◽

pp. 2022-2029 ◽

Cited By ~ 17

Author(s):

Anne Maurer-Cecchini ◽

Saskia Decuypere ◽

François Chappuis ◽

Coralie Alexandrenne ◽

Simonne De Doncker ◽

...

Keyword(s):

T Cell ◽

Poor Response ◽

Interleukin 10 ◽

Response To Treatment ◽

Necrosis Factor Alpha ◽

Reverse Transcription Pcr ◽

Factor Alpha ◽

Complex Relationships ◽

Cytokine Mrnas ◽

Necrosis Factor

ABSTRACT The mechanisms linking the immune response to cutaneous and mucosal leishmaniasis (CL and ML, respectively) lesions and the response to treatment are incompletely understood. Our aims were to prospectively assess, by quantitative reverse transcription-PCR, the levels of mRNA for gamma interferon, tumor necrosis factor alpha, interleukin-10 (IL-10), IL-4, and IL-13, as well as the presence of T cells (CD2) and macrophages (CD68), in CL and ML lesions and to follow their changes in response to treatment with pentavalent antimonials. The leishmanin skin test (LST) was performed on all CL and ML patients before treatment. The patient population included individuals living in areas of Peru where the disease is endemic, i.e., 129 with CL and 43 with ML. Compared to CL patients, the LST induration size was larger, the levels of all cytokine mRNAs but IL-10 were higher, T-cell mRNA was similar, and macrophage mRNA was lower in ML patients. The proportion of CL patients with an LST induration size of >8 mm was higher among responders to treatment. In CL, the pretreatment levels of cytokine mRNAs did not discriminate between responders and nonresponders; however, treatment was more often accompanied by a reduction in the levels of T-cell and cytokine mRNAs in responders than in nonresponders. Furthermore, the production of cytokines per T cell and macrophage decreased with treatment but IL-10 production remained high in nonresponders. Overall, these findings point to complex relationships among New World Leishmania parasites, skin and mucosal immune responses, and treatment outcome. The persistence of high levels of IL-10 in CL is characteristically associated with a poor response to treatment.

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A Comparison Of Hemostatic and Inflammatory Markers In Overt and Non-Overt DIC

Blood ◽

10.1182/blood.v122.21.3577.3577 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3577-3577

Author(s):

Debra Hoppensteadt ◽

Kazuhisa Tsuruta ◽

Joe Hirman ◽

Inder Kaul ◽

Yutaka Osawa ◽

...

Keyword(s):

Inflammatory Cytokines ◽

Research Funding ◽

Protein C ◽

Plasminogen Activator Inhibitor ◽

Interleukin 10 ◽

Plasminogen Activator Inhibitor 1 ◽

Double Blind ◽

Hemostatic System ◽

Recombinant Thrombomodulin ◽

Pai 1

Abstract Disseminated intravascular coagulation (DIC) is a complex pathophysiologic syndrome with marked alterations in the hemostatic system, which may lead to microvascular thrombosis and multi-organ failure. The International Society of Thrombosis and Hemostasis (ISTH) classifies DIC into two distinct categories; overt and non-overt DIC (NO). Overt DIC is characterized by a decompensated hemostatic system whereas non-overt is characterized as a stressed, compensated system. DIC is a frequently observed in sepsis patients. An association between the hemostatic aberrations and inflammation has been previously reported. Therefore we studied the level of hemostatic activation and inflammation in patients with sepsis and suspected DIC enrolled in the ART-123, Phase 2b study. The level of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO), and circulating levels of hemostatic markers including protein C inhibitor (PCI), plasminogen activator inhibitor 1 (PAI-1), and protein C (Pr C) were evaluated in 617 subjects enrolled in a randomized, double-blind, placebo-controlled, Phase-2b study evaluating the safety and efficacy of recombinant thrombomodulin (ART-123) in subjects with sepsis and suspected DIC. When the subjects with overt DIC and with NO DIC were compared, the PrC level was lower and PCT, PAI-1, IL-6 and IL-10 levels were higher, in the overt DIC subjects (Table). The upregulation of the inflammatory cytokines observed in this study may contribute to the decreased levels of Pr C. Inflammatory cytokines may dysregulate the endothelial thrombomodulin resulting impaired hemostatic regulation. Pr C levels are also low due to consumption and impaired synthesis, especially in the overt DIC patients. These results suggest that profiling these mediators may be useful in the diagnostic and prognostic management of sepsis and differentiation between overt and non-overt DIC.BiomarkerGroupNMeanSEMMedianP ValuePr C (%)Normal4094.52.491.80.0043Overt9824.71.828.30.0043NO15746.52.637.00.0043PCTNormal240.260.020.270.0001(ng/ml)Overt9836.87.011.220.0001NO51918.031.45.330.0001PAI-1Normal3120.62.118.7<0.0001(ng/ml)Overt98232.925.0137.5<0.0001NO519147.18.676.0<0.0001Il-6Normal306.80.536.10.0003(pg/ml)Overt981017.6121.7374.40.0003NO519576.739.6174.70.0003IL-10Normal3210.42.43.50.0049(pg/ml)Overt98187.339.146.00.0049NO518108.114.831.00.0049 Disclosures: Hoppensteadt: Asahi Kasei Pharma: Research Funding. Tsuruta:Asahi Kasei Pharma: Employment. Hirman:Asahi Kasei Pharma: Consultancy. Kaul:Asahi Kasei Pharma: Employment. Osawa:Asahi Kasei Pharma: Employment. Fareed:Asahi Kasei Pharma: Research Funding.

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Genetic markers of inflammation may not contribute to metabolic traits in Mexican children

PeerJ ◽

10.7717/peerj.2090 ◽

2016 ◽

Vol 4 ◽

pp. e2090 ◽

Cited By ~ 4

Author(s):

Neeti Vashi ◽

Carolina Stryjecki ◽

Jesus Peralta-Romero ◽

Fernando Suarez ◽

Jaime Gomez-Zamudio ◽

...

Keyword(s):

Leptin Receptor ◽

Interleukin 10 ◽

P Value ◽

Low Grade ◽

Nucleotide Polymorphisms ◽

Necrosis Factor Alpha ◽

Metabolic Complications ◽

Metabolic Traits ◽

Mexican Children ◽

Markers Of Inflammation

Background:Low-grade chronic inflammation is a common feature of obesity and its cardio-metabolic complications. However, little is known about a possible causal role of inflammation in metabolic disorders. Mexico is among the countries with the highest obesity rates in the world and the admixed Mexican population is a relevant sample due to high levels of genetic diversity.Methods:Here, we studied 1,462 Mexican children recruited from Mexico City. Six genetic variants in five inflammation-related genes were genotyped: rs1137101 (leptin receptor (LEPR)), rs7305618 (hepatocyte nuclear factor 1 alpha (HNF1A)), rs1800629 (tumor necrosis factor alpha (TNFA)), rs1800896, rs1800871 (interleukin-10 (IL-10)), rs1862513 (resistin (RETN)). Ten continuous and eight binary traits were assessed. Linear and logistic regression models were used adjusting for age, sex, and recruitment centre.Results:We found that one SNP displayed a nominal evidence of association with a continuous trait: rs1800871 (IL-10) with LDL (beta = −0.068 ± 1.006, P = 0.01). Subsequently, we found one nominal association with a binary trait: rs7305618 (HNF1A) with family history of hypertension (odds-ratio = 1.389 [1.054–1.829], P = 0.02). However, no P-value passed the Bonferroni correction for multiple testing.Discussion:Our data in a Mexican children population are consistent with previous reports in European adults in failing to demonstrate an association between inflammation-associated single nucleotide polymorphisms (SNPs) and metabolic traits.

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Fibrinolytic Dysregulation Contributes to the Hypercoagulable State in Pulmonary Embolism Patients

Blood ◽

10.1182/blood-2021-153380 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3177-3177

Author(s):

Fakiha Siddiqui ◽

Amir Darki ◽

Emily Bontekoe ◽

Yevgeniy Brailovsky ◽

Omer Iqbal ◽

...

Keyword(s):

Pulmonary Embolism ◽

Protein C ◽

Conflicts Of Interest ◽

Plasma Samples ◽

Pronounced Increase ◽

Individual Parameter ◽

Clot Burden ◽

Control Plasma ◽

Pai 1 ◽

D Dimer

Abstract Introduction: The multifactorial and complex pathophysiology of pulmonary embolism (PE) involves dysregulation of hemostatic system including fibrinolytic imbalance, endothelial compromise and generation of thrombotic mediators, along with cellular defects and hemodynamic derangement. It is estimated that 6000 cases of pulmonary embolism and DVT are reported yearly of which 1000 result in death. PE evolves from a pre-existing venous thrombus, obstructing pulmonary artery leading to pulmonary failure. The progression of clot formation results in increase in right ventricular pressure, systemic hypoperfusion, hypoxemia ischemia and eventually multi organ failure. Fibrinolytic dysregulation and generation of procoagulant mediators result in increased clot burden and lead to adverse outcomes. Profiling of the component of the fibrinolytic system for such mediators as the activators and inhibitors of fibrinolysis, vWF and cellular microparticles may provide additional insights into the pathogenesis of PE. The purpose of this study is to profile plasma samples from PE patients for various mediators of hemostatic dysregulation which contribute to the fibrinolytic dysregulation in PE patients. Material & Method: Seventy-eight patients of 18 years or older age, were included in this study through enrolment conducted in conjunction with an ongoing IRB approved project by the pulmonary embolism response team (PERT) registry. Diagnosis of PE was confirmed by computed tomography (CT), angiography or ventilation perfusion imaging. Blood samples were drawn with in 24 hours of confirmed diagnosis of acute PE in 3.2% sodium citrate tubes at the time of diagnosis, processed for platelet poor plasma and frozen. Control plasma samples were obtained from 50 healthy individuals. Both the patient and control plasma samples were analyzed for D-Dimer, PAI-1 antigen, tPA, TAFI-a, protein C, alpha-2 antiplasmin, microparticles and vWF using ELISA methods (Hypen Biomedical, Franklin, Ohio). A functional PAI-1 chromogenic substrate method and an ELISA based uPA antigen method was used (Biomedica, Halifax, Nova Scotia, Canada). Circulating levels of each of the individual biomarkers were compared to normal plasma, descriptive statistics including non-parametric Mann-Whitney t-test and spearman correlation coefficient analysis was carried out by using GraphPad Prism software. Percent Increase from the normal mean was calculated for each individual parameter. p value <0.05 was considered statistically significant. Result: In comparison to normal group, the PE patients exhibited varying levels of increase in the D-Dimer, tPA, uPA, PAI-1 antigen, PAI-1 functional, TAFI antigen, microparticles and vWF, whereas decreased levels were noted for protein C and alpha-2 antiplasmin as shown on Figure 1. D-Dimer showed the most pronounced increase (368.2-fold) followed by tPA (165.9-fold), PAI-1 antigen (3.91-fold), microparticles (2.14-fold), vWF (1.83-fold), uPA (0.5-fold), TAFI antigen (0.40-fold) and PAI-1 functional (0.34-fold). In correlation analysis, D-Dimer negatively correlated with TAFI antigen (r= -0.3106) and alpha-2 antiplasmin (r= -0.3056), functional PAI-1 levels positively correlated with tPA (r= 0.3117) and protein C (r= 0.4059), tPA negatively correlated with TAFI antigen (r= -0.4601), alpha-2 antiplasmin (r= -0.2460) and positively correlated with microparticles (r= 0.2456) , TAFI antigen positively correlated with protein C (r= 0.3612), alpha-2 antiplasmin (r= 0.3899) and negatively correlated with microparticles (r= -0.2470) whereas protein C showed a negative correlation with vWF (r= -0.2838). Conclusion: The markedly increased D-Dimer levels suggest increase clot burden in PE patients. tPA antigen is also markedly increased, whereas the uPA showed modest increase which may suggest compensatory upregulation, PAI-1 antigen levels were much higher in comparison to PAI-1 functional activity, suggesting consumption of this inhibitor. Decreased alpha-2 antiplasmin and protein C levels also suggest consumption. Increased TAFI antigen contribute to the clot resistant to fibrinolysis. Cellular consumption and endothelial dysfunction results in increased in vWF and microparticles promoting thrombogenesis. Measurement of these biomarkers may be useful in the understanding of the pathogenesis, risk stratification and clinical management of PE patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Activated Protein C Increases Fibrin Clot Lysis by Neutralization of Plasminogen Activator Inhibitor No Evidence for a Cofactor Role of Protein S

Thrombosis and Haemostasis ◽

10.1055/s-0038-1647055 ◽

1988 ◽

Vol 60 (02) ◽

pp. 328-333 ◽

Cited By ~ 44

Author(s):

N J de Fouw ◽

Y F de Jong ◽

F Haverkate ◽

R M Bertina

Keyword(s):

Plasminogen Activator ◽

Protein C ◽

Blood Platelets ◽

Plasminogen Activator Inhibitor ◽

Protein S ◽

Tissue Type ◽

Clot Lysis ◽

Activator Inhibitor ◽

Pai 1

summaryThe effect of purified human activated protein G (APC) on fibrinolysis was studied using a clot iysis system consisting of purified glu-plasminogen, tissue-type plasminogen activator, plasminogen activator inhibitor (released from endothelial cells or blood platelets), fibrinogen, 125T-fibrinogen and thrombin. All proteins were of human origin.In this system APC could increase fibrinolysis in a dose dependent way, without affecting fibrin formation or fibrin crosslinking. However, this profibrinolytic effect of APC could only be observed when plasminogen activator inhibitor (PAI-l) was present. The effect of APC was completely quenched by pretreatment of APC with anti-protein C IgG or di-isopropylfluorophosphate. Addition of the cofactors of APC:protein S, Ca2+-ions and phospholipid-alone or in combination did not enhance the profibrinolytic effect of APC. These observations indicate that human APC can accelerate in vitro clot lysis by the inactivation of PAI-1 activity. However, the neutralization of PAI-1 by APC is independent of the presence or absence of protein S, phospholipid and Ca2+-ions.

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Critical limb ischemia patients clinically improving with medical treatment have lower neutrophil-to-lymphocyte and platelet-to-lymphocyte ratios

Vascular ◽

10.1177/1708538120986294 ◽

2021 ◽

pp. 170853812098629

Author(s):

Sevinç B Erdoğan ◽

Ümmühan N Selçuk ◽

Murat Baştopçu ◽

Gökhan Arslanhan ◽

Arif Y Çakmak ◽

...

Keyword(s):

Risk Factors ◽

Medical Treatment ◽

Critical Limb Ischemia ◽

Limb Ischemia ◽

Response To Treatment ◽

Standard Regimen ◽

Markers Of Inflammation ◽

Endovascular Revascularization ◽

Cardiovascular Center ◽

Associated Risk Factors

Objectives Inflammation is a component in the pathogenesis of critical limb ischemia. We aimed to assess how inflammation affects response to treatment in patients treated for critical limb ischemia using neutrophil-to-lymphocyte (NLR) and platelet-to-lymphocytes ratios (PLR) as markers of inflammation. Methods Patients in a single tertiary cardiovascular center with critical limb ischemia unsuitable for surgical or interventional revascularization were retrospectively identified. Data were collected on medical history for risk factors, previous surgical or endovascular revascularization, and outcome. A standard regimen of low molecular weight heparin, aspirin, statins, iloprost infusions, and a standard pain medication protocol were applied to each patient per hospital protocol. Patients with improvement in ischemic pain and healed ulcers made up the responders group and cases with no worsening pain or ulcer size or progression to minor or major amputations made up the non-responders group. Responders and Non-responders were compared for risk factors including pretreatment NLR and PLR. Results 268 included patients who were not candidates for surgical or endovascular revascularization were identified. Responders had significantly lower pretreatment NLR (4.48 vs 8.47, p < 0.001) and PLR (162.19 vs 225.43, p = 0.001) values. After controlling for associated risk factors NLR ≥ 4.63 (p < 0.001) and PLR ≥ 151.24 (p = 0.016) were independently associated with no response to treatment. Conclusions Neutrophil-to-lymphocyte ratio and platelet-to-lymphocytes ratio are markers of inflammation that are reduced in patients improving with medical treatment suggesting a decreased state of inflammation before treatment in responding patients.

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Effects and Responsiveness of a Multicomponent Intervention on Body Composition, Physical Fitness and Leptin in Overweight/Obese Adolescents

International Journal of Environmental Research and Public Health ◽

10.3390/ijerph18147267 ◽

2021 ◽

Vol 18 (14) ◽

pp. 7267

Author(s):

Leticia Borfe ◽

Caroline Brand ◽

Letícia Schneiders ◽

Jorge Mota ◽

Claudia Cavaglieri ◽

...

Keyword(s):

Body Composition ◽

Physical Fitness ◽

Intervention Group ◽

Interleukin 10 ◽

Control Group ◽

Post Intervention ◽

Necrosis Factor Alpha ◽

Obese Adolescents ◽

Quasi Experimental ◽

Multicomponent Program

Physical exercise reduces the biochemical markers of obesity, but the effects of multicomponent interventions on these markers should be explored. The present study aimed to elucidate how overweight/obese adolescents respond to a multicomponent program approach on body composition, physical fitness, and inflammatory markers, using a quasi-experimental study with 33 overweight/obesity adolescents (control group (CG) = 16; intervention group (IG) = 17). The intervention consisted of 24 weeks with physical exercises and nutritional and psychological guidance. Both groups were evaluated at the pre/post-intervention moments on body mass index (BMI); body fat (%Fat); waist circumference (WC); waist/hip ratio (WHR); waist-to-height ratio (WHtR), cardiorespiratory fitness (CRF); abdominal strength, flexibility; leptin; interleukin 6; interleukin 10; and tumor necrosis factor-alpha. Mixed-analysis of variance and generalized estimation equations were used for statistical analysis. There was an interaction effect between groups and time on %Fat (p = 0.002), WC (p = 0.023), WHR (p < 0.001), WHtR (p = 0.035), CRF (p = 0.050), and leptin (p = 0.026). Adolescents were classified as 82.4% responders for %Fat, 70.6% for WC, 88.2% for WHR, and 70.6% for CRF. Further, there was an association between changes in %Fat (p = 0.033), WC (p = 0.032), and WHR (p = 0.033) between responders and non-responders with CRF in the IG. There was a positive effect on body composition, physical fitness, and leptin. In addition, reductions in body composition parameters were explained by CRF improvements.

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Comparison of biomarkers of endothelial dysfunction and microvascular endothelial function in patients with primary aldosteronism and essential hypertension

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320321999491 ◽

2021 ◽

Vol 22 (1) ◽

pp. 147032032199949

Author(s):

Miaomiao Sang ◽

Yu Fu ◽

Chenmin Wei ◽

Jing Yang ◽

Xueting Qiu ◽

...

Keyword(s):

Essential Hypertension ◽

Endothelial Dysfunction ◽

Endothelial Function ◽

Primary Aldosteronism ◽

Cardiovascular Events ◽

Statistical Significance ◽

Enzyme Linked Immunosorbent Assay ◽

Microvascular Endothelial ◽

Pai 1 ◽

Microvascular Endothelial Function

Introduction: Studies have shown that primary aldosteronism (PA) has a higher risk of cardiovascular events than essential hypertension (EH). Endothelial dysfunction is an independent predictor of cardiovascular events. Whether PA and EH differ in the endothelial dysfunction is uncertain. Our study was designed to investigate the levels of biomarkers of endothelial dysfunction (Asymmetric dimethylarginine, ADMA; E-selectin, and Plasminogen activator inhibitor-1, PAI-1) and assess the microvascular endothelial function in patients with PA and EH, respectively. Methods: The biomarkers of endothelial dysfunction were measured by enzyme-linked immunosorbent assay (ELISA). Microvascular endothelial function was evaluated by Pulse amplitude tonometry (PAT). Results: Thirty-one subjects with EH and 36 subjects with PA including 22 with aldosterone-producing adenoma (APA) and 14 with idiopathic hyperaldosteronism (IHA) were enrolled in our study. The ADMA levels among the three groups were different (APA 47.83 (27.50, 87.74) ng/ml vs EH 25.08 (22.44, 39.79) ng/ml vs IHA 26.00 (22.23, 33.75) ng/ml; p = 0.04), however, when the APA group was compared with EH and IHA group, there was no statistical significance (47.83 (27.50, 87.74) ng/ml vs 25.08 (22.44, 39.79) ng/ml for EH, p = 0.11; 47.83 (27.50, 87.74) ng/ml vs IHA 26.00 (33.75) ng/ml, p = 0.07). The results of ADMA levels are presented as Median (p25, p75). Whereas, levels of PAI-1 and E-selectin, microvascular endothelial function were not significantly different between PA and EH subjects. Conclusions: Our study shows no significant differences between PA and EH in terms of biomarkers of endothelial dysfunction and microvascular endothelial function. The microvascular endothelial function of PA and EH patients is comparable.

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Genetic Variations in Tumor Necrosis Factor Alpha, Interleukin-10 Genes, and Migraine Susceptibility

Pain Medicine ◽

10.1111/j.1526-4637.2011.01200.x ◽

2011 ◽

Vol 12 (10) ◽

pp. 1464-1469 ◽

Cited By ~ 13

Author(s):

Omer Ates ◽

Semiha Kurt ◽

Julide Altinisik ◽

Hatice Karaer ◽

Saime Sezer

Keyword(s):

Tumor Necrosis Factor ◽

Tumor Necrosis Factor Alpha ◽

Tumor Necrosis ◽

Interleukin 10 ◽

Genetic Variations ◽

Necrosis Factor Alpha ◽

Factor Alpha ◽

Necrosis Factor

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Antithrombotic, procoagulant, and fibrinolytic mechanisms in cerebral circulation: implications for brain injury and protection

Neurosurgical FOCUS ◽

10.3171/foc.1997.2.6.8 ◽

1997 ◽

Vol 2 (6) ◽

pp. E7 ◽

Cited By ~ 9

Author(s):

Berislav V. Zlokovic

Keyword(s):

Brain Injury ◽

Tissue Factor ◽

Plasminogen Activator ◽

Protein C ◽

Molecular Mechanisms ◽

Biological Significance ◽

Brain Protection ◽

Ischemic Insult ◽

The Brain ◽

Pai 1

Maintaining a delicate balance among anticoagulant, procoagulant, and fibrinolytic pathways in the cerebral microcirculation is of major importance for normal cerebral blood flow. Under physiological conditions and in the absence of provocative stimuli, the anticoagulant and fibrinolytic pathways prevail over procoagulant mechanisms. Blood clotting is essential to minimize bleeding and to achieve hemostasis; however, excessive clotting contributes to thrombosis and may predispose the brain to infarction and ischemic stroke. Conversely, excessive bleeding due to enhanced anticoagulatory and fibrinolytic mechanisms could predispose the brain to hemorrhagic stroke. Recent studies in the author's laboratory indicate that brain capillary endothelium in vivo produces thrombomodulin (TM), a key cofactor in the TM-protein C system that is of major biological significance to the antithrombotic properties of the blood-brain barrier (BBB). The BBB endothelium also expresses tissue plasminogen activator (tPA), a key protein in fibrinolysis, and its rapid inhibitor, plasminogen activator inhibitor (PAI-1). The procoagulant tissue factor is normally dormant at the BBB. There is a vast body of clinical evidence to document the importance of hemostasis in the pathophysiology of brain injury. In particular, functional changes caused by major stroke risk factors in the TM-protein C, tPA/PAI-1, and tissue factor systems at the BBB may result in large and debilitating infarctions following an ischemic insult. Thus, correcting this hemostatic imbalance could ameliorate drastic CBF reductions at the time of ischemic insult, ultimately resulting in brain protection. Delineation of the molecular mechanisms of BBB-mediated hemostasis will likely contribute to future stroke prevention efforts and brain protection strategies.

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