Biochip Array Analysis of Various Mediators of Inflammation in Disseminated Intravascular Coagulation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2302-2302 ◽  
Author(s):  
Saud Rahman ◽  
Debra Hoppensteadt ◽  
Josephine Cunanan ◽  
Rachael Davis ◽  
Nasir Sadeghi ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Conflicts Of Interest ◽  
Vascular Dysfunction ◽  
Tumor Necrosis Factor Receptor ◽  
Neuron Specific Enolase ◽  
Endothelial Damage ◽  
Intravascular Coagulation ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Mediators Of Inflammation ◽  
Circulating Levels

Abstract Abstract 2302 Disseminated intravascular coagulation is a polypathologic syndrome which involves blood, endothelial and target organ dysfunction resulting in the generation of various mediators of vascular dysfunction, hemostatic aberrations and hemodynamic disturbances. In addition, various disorders of target organs such as kidney, liver, heart and brain are observed. Uncontrolled protease generation results in the formation of various mediators of inflammation such as neuron specific enolase (NSE), neutrophil gelatinase associated lipocalin (NGal) and soluble tumor necrosis factor receptor 1 (TNF R1). Endothelial damage results in the generation of thrombomodulin (TM) and endogenous coagulation/fibrinolysis results in D- Dimer formation. In order to study the circulating levels of these mediators, a Biochip array method (Randox, Oceanside, CA) was utilized with samples obtained from clinically diagnosed DIC (n=100) and normal individuals (n=10). The results are summarized in the following table. Circulating levels of these mediators were markedly increased in DIC patients in comparison to normals. The most striking increase was noted in NGal (4–6 fold) and TNF R1 (10 fold). Other mediators were also increased in the DIC group, however the data was broadly scattered. These results indicate that beside the aberration in the hemostatic system NGal and TNF R1 along with other inflammatory mediators may play a major role in the pathophysiology of DIC.MarkerNormal ControlsDIC BaselineCRP (ug/ml)3.47 + 0.913.11 + 0.2*NSE (ng/ml)6.11 + 8.610.78 + 1.6*NGAL(ng/ml)306.45 + 25.51376.56 + 48.5*TNFR1 (ng/ml)0.35 + 0.013.89 + 0.3*DD (ng/ml)232.8 + 74.41318.94 + 80.5*TM (ng/ml)3.4 + 0.33.16 + 0.2 P=<0.05 Disclosures: No relevant conflicts of interest to declare.

Upregulation of Inflammatory Mediators in End-Stage Renal Disease as Measured Using Biochip Array Technology

2011 ◽  
Vol 17 (6) ◽  
pp. E218-E223 ◽  
Author(s):  
Rachael Davis ◽  
Vinod Bansal ◽  
Evangelos Litinas ◽  
Debra Hoppensteadt ◽  
Indermohan Thethi ◽  
...  
Keyword(s):  
Renal Disease ◽  
End Stage Renal Disease ◽  
Tumor Necrosis Factor Receptor ◽  
Neuron Specific Enolase ◽  
Endothelial Damage ◽  
Neutrophil Gelatinase Associated Lipocalin ◽  
Reactive Protein ◽  
Stage Renal Disease ◽  
End Stage ◽  
Neutrophil Gelatinase

Systemic vascular changes contribute to both the pathogenesis and thrombotic comorbidities of end-stage renal disease (ESRD). This study aims to profile various biomarkers and better understand their role in the pathogenesis of ESRD. Plasma samples from 49 patients with ESRD and 56 control individuals were analyzed for markers for inflammation, specifically C-reactive protein (CRP), tumor necrosis factor receptor 1 (TNFR1), neutrophil gelatinase-associated lipocalin (NGAL); thrombomodulin (TM); neuron-specific enolase (NSE), and thrombosis-D-dimer (DD). Compared to controls, all markers studied showed a statistically significant upregulation in patients with ESRD. These results indicate a polypathologic process in patients with ESRD, leading to cardiovascular and cerebrovascular events. However, the clinical significance of previously untested markers, such as TNFR1, NGAL, and NSE, still needs to be further explored. This study further validates the role of endothelial damage and endogenous thrombotic processes in ESRD as evidenced by the increased levels of TM and DD.

scholarly journals Endothelial Dysfunction Is Associated with Mortality and Severity of Coagulopathy in Patients with Sepsis and Disseminated Intravascular Coagulation

2019 ◽  
Vol 25 ◽  
pp. 107602961985216 ◽  
Author(s):  
Amanda Walborn ◽  
Matthew Rondina ◽  
Michael Mosier ◽  
Jawed Fareed ◽  
Debra Hoppensteadt
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Protein C ◽  
High Mobility ◽  
Severity Of Illness ◽  
Endothelial Activation ◽  
Endothelial Damage ◽  
Intravascular Coagulation ◽  
Angiopoietin 2 ◽  
Von Willebrand ◽  
Relationship Of

The role of the endothelium in sepsis-associated disseminated intravascular coagulation (DIC) is multifaceted and may contribute substantially to disease severity and outcome. The purpose of this study was to quantify measures of endothelial function, including markers of activation (endocan, Angiopoietin-2 [Ang-2], and von Willebrand Factor), endogenous anticoagulants (tissue factor pathway inhibitor and protein C), and damage-associated factors (High Mobility Group Box 1 [HMGB-1]) in the plasma of patients with sepsis and DIC, and to determine the relationship of these factors with severity of illness and outcome. Plasma samples were collected from 103 adult patients with sepsis within 48 hours of intensive care unit admission. Biomarker levels were measured using commercially available, standardized methods. Disseminated intravascular coagulation was diagnosed according to the International Society of Thrombosis and Hemostasis scoring algorithm. Twenty-eight-day mortality was used as the primary end point. In this study, endothelial damage and dysfunction were associated with the severity of coagulopathy and mortality in DIC patients. Loss of the endogenous anticoagulant protein C and elevation in the vascular regulator Ang-2 were associated with the development of overt DIC. In addition to Ang-2 and protein C, endocan, a biomarker of endothelial activation, and HMGB-1, a mediator of endothelial damage and activation, were significantly associated with mortality. This underscores the contribution of the endothelium to the pathogenesis of sepsis-associated DIC.

Dysregulation of Inflammatory and Hemostatic Markers in Sepsis Associated Disseminated Intravascular Coagulation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2223-2223 ◽  
Author(s):  
Jawed Fareed ◽  
Debra Hoppensteadt ◽  
Josephine Cunanan ◽  
Michael Mosier ◽  
Yutaka Osawa ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Inflammatory Mediators ◽  
Protein C ◽  
Control Group ◽  
Functional Protein ◽  
Double Blind ◽  
Intravascular Coagulation ◽  
Hemostatic Markers ◽  
Circulating Levels ◽  
Pai 1

Abstract Abstract 2223 Disseminated intravascular coagulation (DIC) represents a complex pathophysiologic syndrome where marked alterations in the hemostatic system are manifested. As a result several inflammatory mediators are up regulated through multiple mechanisms. The up regulation of inflammatory mediators such as anaphylatoxin C5a (C5a), procalcitonin (PCT), interleukin 6 (IL-6), interleukin 10 (IL-10), myeloperoxidase (MPO), C reactive protein (CRP), 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 758 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. Thirty healthy male and female volunteers served as the control group. Commercially available ELISA methods were used to measure the various mediators. Marked deviations in the circulating levels of these markers, as compared to controls, were noted as shown in the following table. Compared with controls, subjects in DIC showed an increase in the circulating levels of most inflammatory markers. The levels of PCT, IL-6 and CRP, where considerably higher in the DIC subjects whereas PCI, Pr C and AT exhibited slight decreases. Wide individual variations were present. The PAI-1 levels were also increased in the DIC subjects. These results are tabulated below. These results clearly indicate that inflammation and impairment of fibrinolysis play a key role in the pathogenesis of DIC Parameter Nomal (NHP Mean+SEM) DIC (Baseline Mean+SEM) % Change Protein C (% Ag) 82.5 ± 13.6 47.6 ± 23.7 −42.2% Functional Protein C (%) 83.4 ± 13.2 46.2 ± 29.8 −44.6% PCI (% Inhibition) 130.0 ± 24.6 79.4 ± 105.5 −38.9% PAI-1 (ng/ml) 35.4 ± 10.8 140.6 ± 165.6 297.1% CRP (ug/ml) 2.6 ± 0.4 48.0 ± 14.2 1736.9% C5a (ng/ml) 9.2 ± 3.2 17.2 ± 13.3 85.1% IL-6 (pg/ml) 9.3 ± 3.7 620.3 ± 1883.4 6583.9% IL-10 (pg/ml) 13.9 ± 13.1 130.2 ± 118.6 836.1% MPO (ng/ml) 16.0 ± 4.2 108.1 ± 68.6 574.6% PCT (ng/ml) 0.2 ± 0.13 21.9 ± 43.3 14514.5% Disclosures: Osawa: Asahi Kasei Pharma America Corporation: Employment. Kaul:Asahi Kasei Pharma America Corporation: Employment.

Prevalence of Anti-Heparin Platelet Factor 4 Antibodies in Patients with Disseminated Intravascular Coagulation.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2094-2094
Author(s):  
Jawed Fareed ◽  
He Zhu ◽  
Josephine Cunanan ◽  
Walter Jeske ◽  
Debra Hoppensteadt ◽  
...  
Keyword(s):  
Platelet Activation ◽  
Disseminated Intravascular Coagulation ◽  
Conflicts Of Interest ◽  
Platelet Factor 4 ◽  
Additional Analysis ◽  
Plasma Samples ◽  
Platelet Factor ◽  
Intravascular Coagulation ◽  
Activation Products ◽  
Low Levels

Abstract Abstract 2094 Poster Board II-71 Disseminated intravascular coagulation (DIC) represents a complex syndrome with multiple pathophysiologic components. Most patients with DIC exhibit thrombocytopenic responses due to endogenous consumption of platelets. A systematic study on the prevalence on anti-heparin platelet factor 4 (AHPF4) antibodies and HIT syndrome in DIC patients has not been presented. To determine the prevalence of AHPF4 antibodies in patients with suspected DIC syndrome a total of 25 plasma samples were retrospectively analyzed utilizing the two commercially available methods (GTI, Brookfield, WI and Hyphen Biomedical, Paris, France). Out of 25 patients, 24 samples were positive for the AHPF4 antibody in the GTI method (OD>0.400), whereas only 16 were positive in the Hyphen Biomedical assay (OD>0.500). Interestingly, only 9 samples were positive in both of these assays. None of the positive samples in either the GTI or the Hyphen assay exhibited a positive 14C serotonin response. Additional analysis of these samples revealed that only 8 of these patients were previously exposed to heparin. Only 4 of the baseline samples were found to contain low levels of heparin as measured by anti-Xa method (< 0.2 U/ml). Additional analysis of these samples revealed the presence of platelet activation products such as platelet factor 4 (PF4), selectin and p-selectin. These studies suggest that circulating AHPF4 antibodies are non-functional and do not produce any thrombocytopenic responses. The elevated circulating PF4 levels and other cytokines may be contributory to the generation of these antibodies in the DIC patients. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Systemic Inflammatory Response Syndrome in Nonhuman Primates Culminating in Multiple Organ Failure, Acute Lung Injury, and Disseminated Intravascular Coagulation

2009 ◽  
Vol 37 (6) ◽  
pp. 799-804 ◽  
Author(s):  
Renee R. Hukkanen ◽  
H. Denny Liggitt ◽  
Robert D. Murnane ◽  
Charles W. Frevert
Keyword(s):  
Systemic Inflammatory Response Syndrome ◽  
Inflammatory Response ◽  
Disseminated Intravascular Coagulation ◽  
Experimental Manipulation ◽  
Endothelial Damage ◽  
Multiple Organ ◽  
Systemic Inflammatory Response ◽  
Major Surgery ◽  
Intravascular Coagulation ◽  
Toxicological Studies

The systemic inflammatory response syndrome (SIRS) is a clinicopathological manifestation of overexuberant acute-phase inflammation caused by infectious or noninfectious etiologies. The systemic release of pro-inflammatory cytokines, chemokines, and lipid and vasoactive mediators induces endothelial damage and microvascular thrombosis, potentially culminating in disseminated intravascular coagulation (DIC), acute respiratory distress syndrome (ARDS), and multiple organ dysfunction (MOD) or failure (MOF). We present five cases in the pig-tailed macaque and olive baboon where SIRS resulted in MOF, ARDS, DIC, and the Waterhouse-Friderichsen syndrome; each with gross and histological elements manifested as edema, deposition of fibrin, hemorrhage, and thrombosis. In the described cases, SIRS was the end-common pathway for multiple risk factors that parallel those documented in humans: major surgery, obstetric complications, and infection. The diagnosis of SIRS should be considered when evaluating nonhuman primate (NHP) cases of MOF manifesting with histological evidence of vascular leakage. Experimental manipulation of NHP models may be complicated by SIRS and accompanying rapid clinical decompensation. Such adverse events may compromise toxicological studies and should be avoided when possible.

scholarly journals Neutrophil Extracellular Traps in the Development of Sepsis-Induced Disseminated Intravascular Coagulation

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1175-1175
Author(s):  
Nicholas Leo Jackson Chornenki ◽  
Dhruva J Dwivedi ◽  
Andrew C Kwong ◽  
Nasim Zamir ◽  
Alison E Fox-Robichaud ◽  
...  
Keyword(s):  
Disseminated Intravascular Coagulation ◽  
Conflicts Of Interest ◽  
Early Recognition ◽  
Critical Role ◽  
Neutrophil Extracellular Traps ◽  
Trauma Patients ◽  
Intravascular Coagulation ◽  
Extracellular Traps ◽  
Inflammatory Stimuli ◽  
Endothelial Cell Death

Abstract Introduction: Disseminated intravascular coagulation (DIC) is an acquired syndrome characterized by widespread intravascular activation of coagulation complicating many conditions including sepsis and traumatic injuries. Early recognition and treatment of DIC is of paramount importance. However, to date no useful markers have been identified that can differentiate "pre-DIC" (which is destined to lead to DIC) from "without-DIC" (in which the hypercoagulable state is transient and does not lead to DIC). Activation of neutrophils by inflammatory stimuli or microbes results in the release of neutrophil extracellular traps (NETs). NETs are web-like structures consisting of cell-free DNA (cfDNA), histones, myeloperoxidase (MPO), and anti-microbial proteins. Although NETs aid in the host response to infection by sequestering pathogens, excessive production of NETs can exert collateral damage to the host by activating coagulation, inhibiting fibrinolysis, and causing endothelial cell death. Recently, sepsis-induced DIC has been shown to correlate with circulating levels of DNA-associated MPO, suggesting that the release of NETs by neutrophils plays a critical role in the onset of DIC. Our objective was to attempt to identify a mechanistic role for NETosis in the development DIC in sepsis and use this information to identify 'pre-DIC' signatures. Methods: Clinical data and biological samples from 357 septic patients who were part of the DNA as a Prognostic Marker in ICU patient (DYNAMICS) study were used. Incidence of DIC was determined using the International Society on Thrombosis and Haemostasis (ISTH) scoring system on Day 1 and each subsequent day. We quantified levels of Citrullinated Histone H3 (H3Cit), a biomarker of NETosis, as well as levels of cfDNA. We also measured levels of Protein C (PC), a natural anticoagulant that prevents blood clotting in the microcirculation. Increased consumption of PC is a hallmark of sepsis and may lead to microvascular thrombosis and DIC. Results: Of the 357 patients included from the DYNAMICS study, 121 were classified as having DIC during the study period: 79 on Day 1 ('overt-DIC') and 42 on a subsequent day ('pre-DIC'). Baseline characteristics of patients are shown in Table 1. Those with DIC had significantly higher baseline APACHE II scores and were significantly more likely to be on vasopressors at admission or have a history of chronic liver disease. DIC was associated with significantly increased mortality (HR= 2.53; 95% CI = 1.62 - 3.93; p < 0.001) even when age and past medical history were controlled for. Levels of PC were significantly reduced in patients with DIC at all time points compared to those without DIC (p < 0.01). However, cfDNA levels did not differ between patients with and without DIC at any timepoint. As cfDNA may be released by multiple mechanisms and sources, H3 Cit was quantified on Day 1 as a marker of NETosis. Levels of H3 Cit on Day 1 were significantly higher in "pre-DIC" and "overt-DIC" patients compared to those 'without DIC' (p<0.05), non-septic, non-trauma ICU Controls (p<0.01), and healthy volunteers (p<0.001) (Figure 1). With respect to differentiating 'pre-DIC' from 'overt-DIC', using Day 1 H3 Cit provided an AUC of 0.66 (0.59-0.74). Higher H3 Cit levels were also correlated with lower PC levels in septic patients (r = -0.124; p = 0.02). In a comparison group of non-septic trauma patients also from the DYNAMICS study; (n=6) patients with DIC did not have significantly different Day 1 H3 Cit from (n=25) trauma patients without DIC (p=0.62) or ICU controls (p=0.99). Conclusion: In sepsis, DIC pathophysiology reflects a consumptive process as indicated by reduced PC levels. NETosis may contribute to this process by producing pro-coagulant stimuli and may prove useful in identifying patients who will develop DIC. As a regulated and targetable process investigations involving NETosis may yield therapies for early treatment of DIC in sepsis. Disclosures No relevant conflicts of interest to declare.

scholarly journals Histopathologic and Electron Microscopic Studies on the Acute Toxicity of Ochratoxin A in Rats

1987 ◽  
Vol 24 (5) ◽  
pp. 427-435 ◽  
Author(s):  
M. A. Albassam ◽  
S. I. Yong ◽  
R. Bhatnagar ◽  
A. K. Sharma ◽  
M. G. Prior
Keyword(s):  
Ochratoxin A ◽  
Disseminated Intravascular Coagulation ◽  
Villous Atrophy ◽  
Endothelial Damage ◽  
Male Rats ◽  
Lymphoid Tissues ◽  
Necrotic Enteritis ◽  
Electron Microscopic ◽  
Intravascular Coagulation ◽  
Glomerular Capillaries

Ochratoxin A was given by gavage to male rats. Moribund and dead animals were necropsied, and the surviving rats, including the controls, were killed 48 hours after dosing. Many of the principal rats were moribund, or began dying, within 12 to 24 hours after dosing. Lesions suggestive of disseminated intravascular coagulation were seen by light microscopy as early as 12 hours after dosing; fibrin deposits were in the spleen, brain choroid plexus, glomerular capillaries, liver, and heart. Renal tubular nephrosis, hepatic and lymphoid necrosis, and necrotic enteritis with villous atrophy were also seen. Electron microscopy demonstrated fibrin strands mixed with degranulated platelets, necrotic leukocytes, and swollen endothelial cells in glomerular capillaries. Myocardial changes included focal supercontracted sarcomeres adjacent to intercalated disks. Swollen sarcolemma, lysed myofibrils and fragmented Z-bands with interstitial edema, vascular thrombosis, and endothelial damage were also seen. The acute pathologic changes induced by ochratoxin A in the intestine, liver, and lymphoid tissues were more obvious than the tubular nephrosis, and the development of a disseminated intravascular coagulation-like syndrome with myocardial changes was a complicating factor.

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