Effects of inflammation on thrombosis and outcomes in COVID-19: secondary analysis of the ATTACC/ACTIV-4a trial.

Background: Patients hospitalized for COVID-19 are at high risk of thrombotic complications and organ failure, and often exhibit severe inflammation, which may contribute to hypercoagulability. Objectives: To determine whether patients hospitalized for COVID-19 experience differing frequencies of thrombotic and organ failure complications and derive variable benefits from therapeutic-dose heparin dependent on the extent of systemic inflammation and whether observed benefit from therapeutic-dose anticoagulation varies depending on the degree of systemic inflammation. Methods: We analyzed data from 1346 patients hospitalized for COVID-19 enrolled in the ATTACC and ACTIV-4a platforms who were randomized to therapeutic-dose heparin or usual care for whom levels of C-reactive protein (CRP) were reported at baseline. Results: Increased CRP was associated with worse patient outcomes, including a >98% posterior probability of increased organ support requirement, hospital length of stay, risk of 28-day mortality, and incidence of major thrombotic events or death (patients with CRP 40-100 mg/L or ≥100 mg/L compared to patients with CRP <40 mg/L). Patients with CRP 40 to 100 mg/L experienced the greatest degree of benefit from treatment with therapeutic doses of unfractionated or low molecular weight heparin compared with usual-care prophylactic doses. This was most significant for an increase in organ support-free days (odds ratio: 1.63; 95% confidence interval, 1.09-2.40; 97.9% posterior probability of beneficial effect), with trends toward benefit for other evaluated outcomes. Conclusion: Moderately ill patients hospitalized for COVID-19 with CRP between 40 mg/L and 100 mg/L derived the greatest benefit from treatment with therapeutic-dose heparin.

Biomarkers of Platelet Activation and Their Prognostic Value in Patients With Sepsis-Associated Disseminated Intravascular Coagulopathy.

Sepsis-associated disseminated intravascular coagulation (DIC) is related to marked hemostatic changes such as transient thrombocytopenia secondary to the endogenous activation and consumption of platelets. This study measured markers of platelet function in 103 adult ICU patients with clinically established sepsis-associated DIC to determine the biomarker association with disease severity. Patients were categorized as having no DIC, nonovert DIC, or overt DIC using the International Society of Thrombosis and Hemostasis scoring system. Plasma levels of CD40L, platelet factor 4 (PF4), platelet-derived microparticles, and microparticle-associated tissue factor were quantified. Markers of platelet activation were significantly elevated in patients with DIC compared to healthy individuals. This increase was independent of platelet count. Levels of PF4 differed based on the severity of DIC and differentiated nonsurvivors and survivors. These findings suggest that the markers of platelet activation in DIC may not be regulated by the number of circulating platelets and may be independent of the factors leading to their consumption.

Plasma MCP-1 levels in bipolar depression during cyclooxygenase-2 inhibitor combination treatment.

BACKGROUND: Neuroinflammation plays a role in the pathophysiology of Bipolar Disorder Depression (BDD) and altered levels of inflammatory mediators, such as monocyte chemoattractant protein-1 (MCP-1, aka CCL2) have been reported. This study reports specifically on MCP-1 levels, as a potential marker of BDD and/or treatment response in patients receiving combination treatment with the cyclooxygenase-2 inhibitor, celecoxib (CBX). METHODS: In this randomized, 10-week, double-blind, two-arm, placebo-controlled study, 47 patients with treatment resistant BDD received either escitalopram (ESC) + CBX, or ESC + placebo (PBO). Plasma MCP-1 levels were measured at 3 time points in the BDD subjects, and in a healthy control (HC) group. Depression severity was quantified using the Hamilton Depression Scale (HAMD-17). RESULTS: The CBX group had significantly lower HAMD-17 scores vs. PBO at week 4 (P = 0.026) and week 8 (P = 0.002). MCP-1 levels were not significantly different in BDD vs. HC subjects at baseline (P = 0.588), nor in CBX vs. PBO groups at week 8 (P = 0.929). Week 8 HAMD-17 scores and MCP-1 levels were significantly negatively correlated in treatment non-responders to CBX or PBO (P = 0.050). Non-responders had significantly lower MCP-1 levels vs. responders at weeks 4 (P = 0.049) and 8 (P = 0.014). MCP-1 was positively correlated with pro-inflammatory analytes in the PBO group and with anti-inflammatory analytes in the CBX group. CONCLUSIONS: Combination treatment reduced treatment resistance and augmented antidepressant response. Baseline plasma MCP-1 levels were not altered in BDD patients. Since non-responders had lower levels of MCP-1, elevated MCP-1 may indicate a better response to CBX + SSRI treatment.

Procalcitonin as a Marker of Comorbid Atrial Fibrillation in Chronic Kidney Disease and History of Sepsis.

Cardiovascular disease and infection are the leading causes of mortality in patients with stage 5 chronic kidney disease on hemodialysis (CKD5-HD). Inflammation is a large component in the pathogenesis of both atrial fibrillation (AF) and sepsis and may link these conditions in CKD5-HD. Procalcitonin (PCT) is an inflammatory biomarker elevated in systemic infection and CKD5-HD, yet its value with regard to comorbid AF has not been thoroughly investigated. The aim of this study sought to evaluate circulating inflammatory markers, including PCT, Angiopoietin-1, Angiopoetin-2, CD40-L, C-reactive protein, d-dimer, and von Willebrand factor in relation to these conditions. Plasma levels of inflammatory markers were measured by enzyme linked immunosorbent assay method in CKD5-HD (n = 97) patients and controls (n = 50). Procalcitonin levels were significantly elevated (P = .0270) in CKD5-HD with comorbid AF compared to those without AF. Further analysis of patients with a history of sepsis demonstrated significantly elevated levels of PCT (P = .0405) in those with comorbid AF (160.7 ± 39.5 pg/mL) compared to those without AF (117.4 ± 25.3 pg/mL). This study demonstrates that the inflammatory biomarker PCT is further elevated in the presence of both AF and a history of sepsis in hemodialysis patients and suggests that underlying chronic inflammation following sepsis resolution may place these patients at greater risk of developing AF.

Development of an Algorithm to Predict Mortality in Patients With Sepsis and Coagulopathy.

Sepsis is a systemic response to infection with a high rate of mortality and complex pathophysiology involving inflammation, infection response, hemostasis, endothelium, and platelets. The purpose of this study was to develop an equation incorporating biomarker levels at intensive care unit (ICU) admission to predict mortality in patients with sepsis, based on the hypothesis that a combination of biomarkers representative of multiple physiological systems would provide improved predictive value. Plasma samples and clinical data were collected from 103 adult patients with sepsis at the time of ICU admission. Biomarker levels were measured using commercially available methods. A 28-day mortality was used as the primary end point. Stepwise linear regression modeling was performed to generate a predictive equation for mortality. Differences in biomarker levels between survivors were quantified using the Mann-Whitney test and the area under the receiver operating curve (AUC) was used to describe predictive ability. Significant differences (P < .05) were observed between survivors and nonsurvivors for plasminogen activator inhibitor 1 (AUC = 0.70), procalcitonin (AUC = 0.77), high mobility group box 1 (AUC = 0.67), interleukin (IL) 6 (AUC = 0.70), IL-8 (AUC = 0.70), protein C (AUC = 0.71), angiopoietin-2 (AUC = 0.76), endocan (AUC = 0.58), and platelet factor 4 (AUC = 0.70). A predictive equation for mortality was generated using stepwise linear regression modeling, which incorporated procalcitonin, vascular endothelial growth factor, the IL-6:IL-10 ratio, endocan, and platelet factor 4, and demonstrated a better predictive value for patient outcome than any individual biomarker (AUC = 0.87). The use of mathematical modeling resulted in the development of a predictive equation for sepsis-associated mortality with performance than any individual biomarker or clinical scoring system which incorporated biomarkers representative of multiple systems.

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

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.

Markers of Inflammation and Infection in Sepsis and Disseminated Intravascular Coagulation.

Sepsis is a severe systemic inflammatory response to infection that manifests with widespread inflammation as well as endothelial and coagulation dysfunction that may lead to hypotension, organ failure, shock, and death. Disseminated intravascular coagulation (DIC) is a complication of sepsis involving systemic activation of the fibrinolytic and coagulation pathways that can lead to multi-organ dysfunction, thrombosis, and bleeding, with a 2-fold increase in mortality. This study demonstrates the diagnostic and prognostic value of profiling various biomarkers of inflammation and infection in patients with sepsis-associated DIC to assess the severity of illness. Deidentified samples were obtained from adult patients with sepsis and suspected DIC. Platelet count, prothrombin time, D-dimer, and fibrinogen levels were used to assign International Society of Thrombosis and Hemostasis DIC scores to plasma samples from 103 patients with sepsis and suspected DIC. Using commercially available enzyme-linked immunosorbent assay, chromogenic assay, and RANDOX Biochip methods, levels of procalcitonin (PCT), extracellular nucleosomes, interleukin (IL) 6, IL-8, IL-10, and tumor necrosis factor α (TNFα) were measured in patients with sepsis and DIC and compared to levels in healthy individuals. Elevated levels of PCT, IL-6, IL-8, IL-10, and TNFα were observed in most patients with sepsis and DIC. Additionally, the levels of these markers show significant positive correlations with each other and with DIC score. Currently, no single biomarker can effectively diagnose DIC in patients with sepsis. This study lays the groundwork for the development of a diagnostic algorithm using several markers of inflammation and infection and DIC score as parameters in assessing severity of sepsis-associated coagulopathy in a clinical setting.

Disseminated Intravascular Coagulation: An Update on Pathogenesis, Diagnosis, and Therapeutic Strategies.

Disseminated intravascular coagulation (DIC) is an acquired clinicobiological syndrome characterized by widespread activation of coagulation leading to fibrin deposition in the vasculature, organ dysfunction, consumption of clotting factors and platelets, and life-threatening hemorrhage. Disseminated intravascular coagulation is provoked by several underlying disorders (sepsis, cancer, trauma, and pregnancy complicated with eclampsia or other calamities). Treatment of the underlying disease and elimination of the trigger mechanism are the cornerstone therapeutic approaches. Therapeutic strategies specific for DIC aim to control activation of blood coagulation and bleeding risk. The clinical trials using DIC as entry criterion are limited. Large randomized, phase III clinical trials have investigated the efficacy of antithrombin (AT), activated protein C (APC), tissue factor pathway inhibitor (TFPI), and thrombomodulin (TM) in patients with sepsis, but the diagnosis of DIC was not part of the inclusion criteria. Treatment with APC reduced 28-day mortality of patients with severe sepsis, including patients retrospectively assigned to a subgroup with sepsis-associated DIC. Treatment with APC did not have any positive effects in other patient groups. The APC treatment increased the bleeding risk in patients with sepsis, which led to the withdrawal of this drug from the market. Treatment with AT failed to reduce 28-day mortality in patients with severe sepsis, but a retrospective subgroup analysis suggested possible efficacy in patients with DIC. Clinical studies with recombinant TFPI or TM have been carried out showing promising results. The efficacy and safety of other anticoagulants (ie, unfractionated heparin, low-molecular-weight heparin) or transfusion of platelet concentrates or clotting factor concentrates have not been objectively assessed.

Biomarker Profiling in Stage 5 Chronic Kidney Disease Identifies the Relationship between Angiopoietin-2 and Atrial Fibrillation.

Atrial fibrillation (AF) is prevalent in nearly 27% of patients with stage 5 chronic kidney disease on hemodialysis (CKD5-HD), suggesting a strong association between these 2 pathologies. It is hypothesized that the relationship between these 2 diseases may be mediated by inflammation. Angiopoietin-2 (Ang-2), a pro-inflammatory biomarker of endothelial instability, inflammation, and vascular remodeling, is elevated in CKD5-HD and AF, yet has not been evaluated in patients with concomitant AF and CKD5-HD. The aim of this study is to analyze circulating levels of inflammatory and thrombotic biomarkers in patients with concomitant AF and CKD5-HD. Plasma levels of Ang-2 were measured via sandwich enzyme-linked immunosorbent assay method in CKD5-HD patients (n = 96), patients with AF (n = 38), and controls (n = 50). Angiopoietin-2 was markedly elevated in CKD5-HD with comorbid AF as compared to CKD5-HD alone, and AF alone, respectively (13.05 ± 1.56 vs 9.57 ± 0.71 ng/mL; P = .00169; vs 2.48 ± 0.57 ng/mL; P < .0001). The results of this study suggest an additive effect of Ang-2 with coexistence of AF and CKD5-HD, which may be useful in the detection of AF within this patient population.

Biomarker Profiling of Neurovascular Diseases in Patients with Stage 5 Chronic Kidney Disease.

Patients with stage 5 chronic kidney disease (CKD5D) have a higher risk of developing neurocognitive deficits. Stroke, cervical carotid artery disease (CCAD), and intracranial atherosclerotic disease (ICAD) are causes of such deficits in CKD5D. Chronic inflammation from renal failure elevates risk for these diseases through oxidative stress and vascular dysfunction. The adverse impact on the carotid and intracranial vasculatures contributes to the multifactorial pathophysiology of stroke. Eleven plasma biomarker levels in patients with CKD5D (n = 97) and healthy controls (n = 17-50) were measured using sandwich enzyme-linked immunosorbent assay (ELISA) method. Of the 97 patients with CKD5D, 24 had CCAD, 19 had ICAD, and 23 had acute stroke. Elevations in NACHT, LRR, and PYD domains-containing protein 3 (NALP3) levels in patients with CKD5D (+)CCAD (1.80 ± 0.11 ng/mL) compared to patients with (-)CCAD (1.55 ± 0.08 ng/mL) were statistically significant (P = .0299). Differences in D-dimer levels were also found to be statistically significant (P = .0258) between CKD5D (+)stroke (1.83 ± 0.42 µg/mL) and (-)stroke (0.89 ± 0.13 µg/mL) groups. The ages of the (+) neurovascular disease groups were found to be significantly elevated compared to the (-) neurovascular disease groups (P = .0002 carotid AD; P < .0001 ICAD; P = .0157 stroke). D-dimer levels were positively correlated with age in CKD5D (P = .0375). With the possible exception of NALP3 for CCAD, profiling levels of specific biomarkers for risk stratification of neurovascular diseases in the CKD5D population warrants further investigation.

Angiopoietin 2 Levels in the Risk Stratification and Mortality Outcome Prediction of Sepsis-Associated Coagulopathy.

It has been well established that angiopoietin 2 (Ang-2), a glycoprotein involved in activation of the endothelium, plays an integral role in the pathophysiology of sepsis and many other inflammatory conditions. However, the role of Ang-2 in sepsis-associated coagulopathy (SAC) specifically has not been defined. The aim of this study was to measure Ang-2 plasma levels in patients with sepsis and suspected disseminated intravascular coagulation (DIC) in order to demonstrate its predictive value in SAC severity determination and 28-day mortality outcome. Plasma samples were collected from 102 patients with sepsis and suspected DIC at intensive care unit (ICU) admission. The Ang-2 plasma levels were quantified using a sandwich enzyme-linked immunosorbent assay method. The International Society on Thrombosis and Haemostasis DIC scoring system was used to compare the accuracy of Ang-2 levels versus clinical illness severity scores in predicting SAC severity. Mean Ang-2 levels in patients with sepsis and DIC were significantly higher in comparison to healthy controls ( P < 0.0001), and median Ang-2 levels showed a downward trend over time ( P = 0.0008). Baseline Ang-2 levels and clinical illness severity scores were higher with increasing severity of disease, and Ang-2 was a better predictor of DIC severity than clinical illness scores. This study demonstrates that Ang-2 levels are significantly upregulated in SAC, and this biomarker can be used to risk stratify patients with sepsis into non-overt DIC and overt DIC. Furthermore, the Ang-2 level at ICU admission in a patient with sepsis and suspected DIC may provide a predictive biomarker for mortality outcome.

International Normalized Ratio Relevance to the Observed Coagulation Abnormalities in Warfarin Treatment and Disseminated Intravascular Coagulation.

The development of coagulation abnormalities is common in patients with sepsis. Sepsis-associated coagulopathy (SAC) is typically diagnosed by prothrombin time (PT) prolongation or elevated international normalized ratio (INR) in conjunction with reduced platelet count. INR is also used to monitor warfarin-treated patients. However, due to the different natures of SAC and warfarin anticoagulation, it is likely that the same INR value provides different information in these two patient populations. The purpose of this study was to compare measures of coagulation function and clotting factor levels in patients with SAC to those observed in patients receiving warfarin anticoagulation. Deidentified plasma samples were collected at baseline from patients diagnosed with SAC and from patients receiving warfarin. These plasma samples were evaluated for PT/INR, activated partial thromboplastin time (aPTT), fibrinogen, and functional and immunologic levels of factors VII, IX, and X. Both aPTT and fibrinogen correlated with INR in patients with SAC, but not in patients treated with warfarin. Factors VII, IX, and X showed an inverse relationship with INR in the anticoagulated patients; however, no relationship between factor level and INR was observed in patients with SAC. Distinct patterns of coagulopathy were observed in patients with SAC and patients receiving warfarin anticoagulation, and equivalent INR values were associated with distinct coagulation profiles in the two patient groups. These results suggest that an abnormal INR provides different information about the coagulation status in patients with disseminated intravascular coagulation than in patients receiving warfarin. This may indicate that an equivalently increased INR predicts different bleeding risks in these two patient groups.

Elevated extracellular nucleosomes and their relevance to inflammation in stage 5 chronic kidney disease.

BACKGROUND: Chronic kidney disease is a disorder characterized by a pro-inflammatory state that is associated with increased morbidity and mortality. Endogenous damage-associated molecular patterns, including nucleosomes, may contribute to this persistent inflammation. The aim of this study was to profile and evaluate the clinical significance of circulating nucleosomes in patients with Stage 5 chronic kidney disease (CKD5) on hemodialysis (HD). METHODS: Under institutional review board approval, plasma samples were collected from 90 CKD5-HD patients (45 male and 45 female) prior to hemodialysis. Normal human plasma samples (25 male and 25 female) were used as a control group. Commercial enzyme-linked immunosorbent and colorimetric assays were used to profile nucleosome levels and biochemical markers of kidney injury, inflammation, thrombosis, and renal function in CKD5-HD and control groups. Clinical laboratory parameters were documented from the electronical medical record and correlated to nucleosome levels in the CKD5-HD cohort. RESULTS: In comparison to healthy volunteers, the plasma from CKD5-HD patients exhibited markedly elevated nucleosomes (P<0.0001). Furthermore, nucleosome levels correlated with WBC count (P=0.025, R=0.243) and CRP (P=0.019, R=0.266) levels. No correlation was found between nucleosomes and the other parameters studied. CONCLUSIONS: Our findings indicate extracellular nucleosomes are significantly elevated in CKD5-HD, suggesting increased cell death and/or inflammation. The observed correlations between nucleosomes and parameters of inflammation is suggestive of a complex, systemic inflammatory process underlying renal deterioration, consistent with the literature. Thus, nucleosomes may play a role in the pathogenesis and outcome of CKD5-HD.

Plasma C-reactive protein levels in bipolar depression during cyclooxygenase-2 inhibitor combination treatment.

Immune system activation and neuroinflammation appear to play a key role in the pathophysiology and treatment of bipolar depression (BDD). This study is the first to analyze blood levels of the pro-inflammatory biomarker C-reactive protein (CRP) in bipolar disorder patients treated with the cyclooxygenase-2 inhibitor, celecoxib (CBX). In this double-blind study, 47 consenting patients with BDD were randomized to receive either escitalopram (10 mg twice/day) + CBX (200 mg twice/day), or escitalopram (10 mg twice/day) + placebo (twice/day). Plasma CRP levels were measured in both patient groups at baseline, week 4, and week 8, and in a healthy control (HC) group of subjects (N = 35) once. Symptoms were rated using the 17-item Hamilton Depression Scale (HAMD-17). The CBX group had significantly lower HAMD-17 scores vs. placebo at week 4 (P = 0.026) and week 8 (P = 0.002). Therefore, SSRI + CBX is more effective than SSRI + placebo in reversing treatment resistance and augmenting antidepressant response in BDD. Baseline CRP levels were significantly increased amongst BDD patients versus HC subjects, indicating that CRP may be a useful biomarker for BDD (P = 0.044). No significant differences in CRP levels were measured between CBX and placebo groups at baseline (P = 0.156), but by week 8 CRP was significantly decreased in the CBX group vs. placebo (P = 0.003). This indicates reduced inflammation in CBX-treated patients, and that CRP may be a useful biomarker for monitoring treatment response in BDD patients during SSRI + CBX combination treatment. CRP and IL-6 levels were positively correlated in the CBX group, and CRP levels were positively correlated with BMI.

Biomarkers of Inflammation, Thrombogenesis, and Collagen Turnover in Patients With Atrial Fibrillation.

The purpose of this study was to determine whether there are any differences in the levels of inflammatory, thrombotic, and collagen turnover biomarkers between individuals with atrial fibrillation (AF) and healthy volunteers. Circulating plasma levels of plasminogen activator inhibitor 1 (PAI-1), CD40-ligand (CD40-L), nucleosomes (which are indicators of cell death), C-reactive protein (CRP), procollagen III N-terminal propeptide (PIIINP), procollagen III C-terminal propeptide (PIIICP), procollagen I N-terminal propeptide, tissue plasminogen activator, and von Willebrand factor were analyzed as potential biomarkers of AF. Baseline plasma was collected from patients with AF prior to ablation surgery at Loyola University Medical Center. Individuals with AF had statistically significantly increased levels of PAI-1, CD40-L, and nucleosomes, when compared to the normal population ( P < .0001). Additionally, there was a statistically significant increase in the CRP ( P = .01), PIIINP ( P = .04), and PIIICP ( P = .0008) when compared to normal individuals. From this study, it is concluded that the prothrombotic, inflammatory, and collagen turnover biomarkers PAI-1, CD40-L, nucleosomes, CRP, PIIICP, and PIIINP are elevated in AF.

Fibrinolytic Deficit and Platelet Activation in Atrial Fibrillation and Their Postablation Modulation.

This study aims to examine the effects of atrial fibrillation (AF) on the expression of the cellular mediators plasminogen activator inhibitor 1 (PAI-1) and CD40 ligand (CD40-L). Additionally, the effect of catheter ablation on the levels of the aforementioned biomarkers was also examined. In this prospective study, plasma samples were collected from patients with AF at baseline prior to ablation and at 1 and 3 months postablation. There was a statistically significant increase in CD40-L at baseline in patients with AF compared to control ( P = .0034). There was a statistically significant decrease in CD40-L levels postablation at both 1 month ( P < .0001) and 3 months ( P < .0001) compared to baseline. Baseline levels of PAI-1 were elevated compared to the control group (mean 19.55 ± 2.17 ng/mL vs 4.85 ± 0.41 ng/mL) and a statistically significant decrease in circulating PAI-1 levels 1 month postablation ( P = .05) was noted compared to preablation levels. These data suggest that inflammation plays an important role in the pathogenesis of AF and that these cellular mediators are modulated by catheter ablation.

Postoperative Changes in the Systemic Inflammatory Milieu in Older Surgical Patients.

Dysregulated inflammation is a central component of wound healing following surgery. We prospectively enrolled older patients (n = 25, age 65 ± 7 years) undergoing elective total knee arthroplasty or total hip arthroplasty secondary to advanced osteoarthritis (OA) and healthy controls (n = 48). Inflammatory, proangiogenic (vascular endothelial growth factor [VEGF], monocyte chemoattractant protein-1 [MCP-1], and interleukin-8 [IL-8]), and antiangiogenic (interferon γ [IFN-γ] and IL-4) factors were measured using a high-sensitivity biochip. Patients with OA had significantly higher baseline VEGF (10.5 ± 1.2 pg/mL vs 4.8 ± 0.2 pg/mL, P < .001), MCP-1 (130.6 ± 7.7 pg/mL vs 88.6 ± 3.9 pg/mL, P < .0001), and IL-8 (4.0 ± 0.5 pg/mL vs 2.6 ± 0.1 pg/mL, P < .05). Postoperatively, the levels of VEGF (10.5 ± 1.2 pg/mL vs 18.8 ± 1.5 pg/mL, P < .001) and MCP-1 (130.6 ± 7.7 pg/mL vs 153.1 ± 11.5 pg/mL, P < .05) increased significantly. Baseline and postoperative MCP-1 levels correlated positively and significantly with age. The levels of IFN-γ and IL-4 (which has anti-inflammatory properties) did not significantly differ at baseline in patients with OA compared to controls and did not significantly rise postoperatively. We conclude that systemic levels of pro-inflammatory and angiogenic proteins are increased in patients with OA and rise further postoperatively, while proteins that restrain inflammation and angiogenesis do not coordinately rise. These findings implicate imbalance in inflammatory pathways in OA that may contribute to its pathobiology.

Biomarker Profile of Sepsis-Associated Coagulopathy Using Biochip Assay for Inflammatory Cytokines.

Disseminated intravascular coagulation (DIC) is a major pathophysiological mechanism of sepsis and greatly increases the risk of death in septic patients. Disseminated intravascular coagulation is a complex physiological phenomenon that involves inappropriate activation of coagulation, inflammation, and endothelial processes. The purpose of this study was to analyze the levels of inflammatory cytokines in the plasma of patients with DIC in order to compare the measured levels with those from healthy individuals, draw correlations, and provide a basis for further biomarker panel development. The inflammatory biomarkers interleukin (IL) 1ß, IL-6, IL-8, IL-10, interferon (IFN) γ, vascular endothelial growth factor (VEGF), tumor necrosis factor (TNF) α, monocyte chemoattractant protein (MCP)-1, and epidermal growth factor (EGF) showed significant ( P < .05) elevation in patients with DIC. Interestingly, while numerous correlations were present between IL-ß, IL-6, IL-8, IL-10, IFN-γ, TNF-α, MCP-1, and many of the inflammatory cytokines measured, VEGF and EGF exhibited much less extensive correlation, suggesting that their involvement in DIC may be independent of the other investigated inflammatory markers.

Biomarker profiling of plasma samples utilizing RANDOX biochip array technology.

RANDOX Biochip Array Technology offers an efficient, cost-effective method of measuring multiple analytes on a large number of samples in biologic fluids. This innovative technology has proven extremely useful in the profiling of markers in a number of different disease states. Biochip arrays have also shown promise in clinical trials, offering rapid evaluation of multiple markers and circulating levels of the analyte with only a small sample. This biochip technology has broad applications in clinical, pharmaceutical, toxicological, immunologic and microbiologic areas. This technique offers parallel profiling and will have great value in personalized and precision medicine. The aim of this manuscript is to explore the recent and future utility of biochips for profiling marker levels in different diseased populations using RANDOX's Biochip Array Technology.

Modulation of Interleukins in Sepsis-Associated Clotting Disorders: Interplay With Hemostatic Derangement.

Interleukins play a central role in the immune system and are involved in a variety of immunological, inflammatory, and infectious disease states including sepsis syndrome. Levels of interleukins may correlate with overall survival and may directly or indirectly affect some of the regulators of coagulation and fibrinolysis, thereby disrupting hemostasis and thrombosis. Our hypothesis is that in sepsis-associated coagulopathies (SACs), interleukins may be upregulated, leading to hemostatic imbalance by generating thrombogenic mediators. We profiled the levels of interleukins IL-1α, IL-1ß, IL-2, IL-4, IL-6, IL-8, and IL-10 in addition to d-dimer (DD) in patients with SAC and in normal donors. We observed the highest increase in interleukins IL-6 (322-fold), IL-8 (48-fold), IL-10 (72-fold), and DD (18-fold). This suggests that interleukins such as IL-6 and IL-10 have a close association with coagulopathy and fibrinolytic dysregulation in sepsis and can be considered as candidates for potential therapeutic targets in SAC.