scholarly journals Plasma levels of S100A8/A9, histone/DNA complexes, and cell‐free DNA predict adverse outcomes of immune thrombotic thrombocytopenic purpura

2021 ◽  
Author(s):  
Jingrui Sui ◽  
Ruinan Lu ◽  
Konstantine Halkidis ◽  
Nicole K. Kocher ◽  
Wenjing Cao ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Plasma Levels ◽  
Adverse Outcomes ◽  
Dna Complexes ◽  
Thrombocytopenic Purpura ◽  
Cell Free Dna ◽  
Free Dna

scholarly journals Plasma Levels of Histone-DNA Complex and Cell-Free DNA Predict Mortality in Patients with Immune Thrombotic Thrombocytopenic Purpura

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1070-1070
Author(s):  
Jingrui (Jean) Sui ◽  
Konstantine Halkidis ◽  
Nicole K. Kocher ◽  
Lance A. Williams ◽  
Radhika Gangaraju ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Mortality Rates ◽  
Proportional Hazard ◽  
Dna Complexes ◽  
Thrombocytopenic Purpura ◽  
Cell Free Dna ◽  
Cox Proportional Hazard ◽  
Free Dna ◽  
Cox Proportional Hazard Regression ◽  
Dna Complex

Background: Deficiency of plasma ADAMTS13 activity resulting from acquired autoantibody against ADAMTS13 is the primary cause of immune thrombotic thrombocytopenic purpura (iTTP). Therapeutic plasma exchange plus corticosteroids and immunosuppression is the standard of care for patients with iTTP. However, mortality rate remains high and clinical factors or laboratory biomarkers that predict mortality are not fully established. Previous studies have demonstrated that plasma levels of histone-DNA complexes and cell-free DNA are dramatically elevated in patients with acute disease but reduced during remission. We hypothesize that elevated histone-DNA complexes or cell-free DNA may have a predictive role for mortality in patients with acute iTTP. Methods: 102 unique patients with a confirmed diagnosis of iTTP who underwent therapeutic plasma exchange (TPE) at UAB-Medical Center from April 2006 to December 2018 were enrolled into the study. Demographic information and laboratory parameters were collected on admission and during the follow-up. Plasma levels of histone-DNA complexes and cell-free DNA were determined by an enzyme-linked immunosorbent assay and PicoGreen dsDNA assay, respectively. Mann-Whitney, Fisher's exact, t test, log-rank test, and Cox proportional hazard regression analysis were performed to determine the significance of each marker in predicting death. Results: In this cohort, age was 44.7 ± 1.3 (mean ± SD) years old, 56.9% were female, 82.4% were African Americans, 61.8% had an initial episode, the median (IQR) body mass index (BMI) was 33.6 (29.3-41.5). 52.9% of patients had hypertension, 21.6% diabetes, 18.6% systemic lupus erythematous and 8.7% HIV. The overall mortality rate was 10.8% (11/102). Plasma levels, median (IQR), of histone-DNA complexes and cell-free DNA on admission were 56.3 (35.8-136.4) AU/mL and 952.2 (799.7-1431.4) ng/mL, respectively. Mann-Whitney test revealed that high plasma levels of histone-DNA complex (≥134.9 U/mL) (p=0.007) and cell-free DNA (≥952.2 ng/mL) (p=0.009) were associated with the increased risks of myocardial injury (e.g. elevated troponin). Cox proportional hazard regression analysis demonstrated that the increased levels of histone-DNA complexes and cell-free DNA were also predictive for the increased mortality rates in patients with iTTP with hazard ratios (HRs) of 4.1 (95% CI, 1.2-13.4) (p=0.02) and 8.5 (95% CI, 2.2-33.3 (p=0.002), respectively. Kaplan-Meier survival analysis revealed significant differences in the disease-free survival rates of patients with high levels (≥75 percentile) vs. low levels (<75 percentile) of plasma histone-DNA complexes and cell-free DNA, respectively (see Fig. 1). Conclusion: Our results demonstrate that the elevated plasma levels of histone-DNA complexes and cell-free DNA predict the worse outcome (e.g. the increased mortality rates) in patients with iTTP. *SD, standard deviation; IQR, interquartile range; 95% CI, 95% confidential interval. Disclosures Zheng: Ablynx/Sanofi: Consultancy, Speakers Bureau; Alexion: Speakers Bureau; Shire/Takeda: Research Funding; Clotsolution: Other: Co-Founder.

Plasma levels of bigEndothelin-1 are associated with renal insufficiency and in-hospital mortality of immune thrombotic thrombocytopenic purpura

2021 ◽  
Author(s):  
Ruinan Lu ◽  
X. Long Zheng
Keyword(s):  
Hospital Mortality ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Plasma Levels ◽  
Thrombus Formation ◽  
Microfluidic Channel ◽  
Thrombocytopenic Purpura ◽  
Severe Deficiency ◽  
Bioactive Product ◽  
First Time

Immune thrombotic thrombocytopenic purpura (iTTP) is caused by severe deficiency of plasma ADAMTS13 activity. Despite advances in early diagnosis and management, the mortality rate of acute iTTP remains high in a large part of world where access to some of the most novel therapies is limited. To determine the role of plasma bigEndothelin-1 (bigET-1) or its bioactive product ET-1 as a biomarker and/or a pathogenic factor in acute iTTP, plasma levels of bigET-1 were determined using an immunoassay in patients with iTTP on admission and during remission, as well as in healthy controls; moreover, the biological effect of ET-1 in thrombus formation was determined by a microfluidic assay. We show that plasma levels of bigET-1 were dramatically increased in patients with acute iTTP on admission, which was significantly decreased during clinical response/remission; elevated admission levels of plasma bigET-1 were associated with low estimated glomerular filtration rate, the need for intensive care unit admission or intubation, and in-hospital mortality. Moreover, an addition of a bioactive product ET-1 to cultured endothelial cells in a microfluidic channel dramatically accelerated the rate of thrombus formation under arterial flow. Our results demonstrate for the first time a potential role of measuring plasma bigET-1 in patients with acute iTTP in assessing the disease severity and risk of in-hospital mortality, which may help stratify patients for a more aggressive monitoring and therapeutic strategy; also, the bioactive ET-1, derived from bigET-1, may result in acute renal injury in TTP patient, likely through its vasoconstriction and prothrombotic properties.

scholarly journals Lung-protective ventilation suppresses plasma levels of cell-free DNA in porcine experimental postoperative sepsis

Critical Care ◽  
2014 ◽  
Vol 18 (Suppl 1) ◽  
pp. P292 ◽  
Author(s):  
A Nyberg ◽  
J Sperber ◽  
M Lipcsey ◽  
J Jylhävä ◽  
M hurme ◽  
...  
Keyword(s):  
Plasma Levels ◽  
Protective Ventilation ◽  
Lung Protective Ventilation ◽  
Postoperative Sepsis ◽  
Cell Free Dna ◽  
Free Dna

scholarly journals Elevated Plasma Levels of Cell‐Free DNA During Liver Transplantation Are Associated With Activation of Coagulation

2020 ◽  
Vol 26 (4) ◽  
pp. 602-603
Author(s):  
Osamu Yoshino ◽  
Vijayaragavan Muralidharan ◽  
Alexander Dobrovic ◽  
Su Kah Goh
Keyword(s):  
Liver Transplantation ◽  
Plasma Levels ◽  
Elevated Plasma ◽  
Cell Free Dna ◽  
Free Dna

High Levels of Circulating Cell-free DNA Are Associated With a Poor Prognosis in Patients With Severe Fever With Thrombocytopenia Syndrome

2019 ◽  
Vol 70 (9) ◽  
pp. 1941-1949 ◽  
Author(s):  
Yue Zhang ◽  
Rui Song ◽  
Yi Shen ◽  
Yongxiang Zhao ◽  
Zhenghua Zhao ◽  
...  
Keyword(s):  
Disease Progression ◽  
Predictive Value ◽  
Viral Infections ◽  
Myocardial Damage ◽  
Predictive Biomarker ◽  
Severe Illness ◽  
Dna Complexes ◽  
Cell Free Dna ◽  
Free Dna ◽  
Severe Fever

AbstractBackgroundThe extensive geographical distribution and high mortality rate of severe fever with thrombocytopenia syndrome (SFTS) have made it an important threat to public health. Neutrophil extracellular traps (NETs) can be activated by a variety of pathogens and are associated with thrombocytopenia in viral infections. We aimed to identify NET production and its predictive value for disease progression and prognosis in patients with SFTS.MethodsA prospective study was performed with a multicenter cohort of patients with SFTS (n = 112) to quantify serum NET levels. Three markers of NETs—namely, cell-free DNA (cfDNA), myeloperoxidase-DNA complexes, and lactoferrin-DNA complexes—were measured with PicoGreen double-stranded DNA assays and enzyme-linked immunosorbent assays. Receiver operating characteristic curves and multivariate regression analyses were performed to calculate the predictive value of cfDNA levels.ResultsSFTS was characterized by pronounced NET formation. The serum levels of NETs changed dynamically during disease progression, with an inverse pattern of the trends of platelet and neutrophil levels. High cfDNA levels were strongly associated with multiple pathological processes, including coagulopathy, myocardial damage, liver dysfunction, and the development of encephalopathy. A high level of cfDNA (&gt;711.7 ng/mL) at the time of the initial diagnosis predicted severe illness in patients with SFTS (odds ratio, 8.285 [95% confidence interval, 2.049–33.503]; P = .003).ConclusionsThis study has a high degree of clinical impact for identification of cfDNA as a useful predictive biomarker of clinical outcomes of SFTS.

Effect of therapeutic plasma exchange on plasma levels of oxidative biomarkers in a patient with thrombotic thrombocytopenic purpura

2014 ◽  
Vol 94 (4) ◽  
pp. 368-373 ◽  
Author(s):  
Sebastiano Gangemi ◽  
Alessandro Allegra ◽  
Paolo Sciarrone ◽  
Sabina Russo ◽  
Mariateresa Cristani ◽  
...  
Keyword(s):  
Plasma Exchange ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Plasma Levels ◽  
Therapeutic Plasma Exchange ◽  
Thrombocytopenic Purpura ◽  
Oxidative Biomarkers

scholarly journals Active and Ultra-Large Von Willebrand Factor Is Significantly Elevated in Patients with Immune Thrombotic Thrombocytopenic Purpura

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 523-523
Author(s):  
Wenjing Cao ◽  
Alicia Veninga ◽  
Elizabeth M. Staley ◽  
Adam Miszta ◽  
Nicole Kocher ◽  
...  
Keyword(s):  
Thrombotic Thrombocytopenic Purpura ◽  
Von Willebrand Factor ◽  
Plasma Levels ◽  
Acute Episode ◽  
Healthy Controls ◽  
Plasma Samples ◽  
Adamts13 Activity ◽  
Thrombocytopenic Purpura ◽  
Von Willebrand ◽  
Willebrand Factor

Abstract Background: Immune thrombotic thrombocytopenic purpura (iTTP), a potentially fatal hematological emergency, is primarily caused by acquired deficiency of ADAMTS13 activity due to autoantibodies. Immunoglobulin G (IgG)-type autoantibodies bind ADAMTS13 and inhibit its ability to cleave endothelium-derived ultra large von Willebrand factor (ULVWF). However, it remains poorly understood whether plasma VWF status can be used as a disease marker for diagnosis and monitoring therapy in patients with acute iTTP. Objective: To address this question, we determined plasma levels of VWF antigen (VWF:Ag), collagen-binding activity (VWF:CB), active forms of VWF (VWF:Ac), and VWF multimers in iTTP patients during acute episode and in early remission. Patients and Methods: From the Alabama registry, we identified 69 unique patients with a confirmed diagnosis of iTTP in whom plasma ADAMTS13 activity was <10 U/dL with positive inhibitors and elevated anti-ADAMTS13 IgGs. Of 69 patients, 21 had longitudinal plasma samples collected. Plasma samples from 56 healthy individuals, who did not have a hematological disease, cancer, and infection, were recruited as controls. Plasma levels of VWF:Ag, VWF:CB, and VWF:Ac were determined by an ELISA-based assay. Plasma VWF multimer distribution was assessed by an in-gel Western blotting assay following electrophoresis on a 1% SDS-agarose gel. Results: The mean age for our cohort iTTP patients was 43.9 ± 13.4 years. Twenty-six patients were male and 43 were female with male to female ratio of 1 to 1.7. Fifty-three patients were African American descents, 14 Caucasians, 1 Hispanic, and 1 unknown race. Plasma levels of VWF:Ag in acute iTTP patients were 289.4 ± 17.7%, significantly increased compared with those in the healthy controls (144.9 ± 7.6%) (p<0.0001); plasma levels of VWF:CB in these patients were 241 ± 17.9%, also significantly elevated compared with those in the healthy controls (149.9 ± 12.01%) (p=0.0001); additionally, plasma levels of VWF:Ac (304.6 ± 23.2%), assessed by its ability to bind anti-VWF-A1 nanobody, were more dramatically elevated compared with those in the controls (101.6 ± 5.9%) (p<0.0001). More interestingly, while the ratios of VWF:CB to VWF:Ag in patients with acute iTTP (0.8 ± 0.04) were lower than those in the healthy controls (1.0 ± 0.05) (p=0.0036), the ratios of VWF:Ac to VWF:Ag were significantly higher in patients with acute episode (1.2 ± 0.1) than those in the controls (0.8 ± 0.05) (p=0.0003). Furthermore, there was no statistically significant difference in the patient plasma levels of VWF:Ag (p=0.69) and VWF:CB (p=0.08) during acute episode and during early remission. However, the plasma levels of VWF:Ac in patients with acute disease were significantly higher than those in the early remission (p=0.002). Surprisingly, 90% (36/40) of out iTTP patients during acute episode showed the presence of ULVWF in their plasma using in-gel Western blotting, which allows the ULVWF to be detected without the transfer step to avoid any potential loss of larger VWF multimers during protein transfer. These ULVWF multimers disappeared in 3/4 iTTP patients in remission when ADAMTS13 activity recovered. In 28 healthy control samples, only one showed ULVWF. Conclusion: Our results demonstrate, for the first time in a large cohort, that active forms of VWF and ultra large VWF multimers are present in iTTP patient's plasma during the acute period, which is reduced or disappears during the early remission. Therefore, measuring active forms of VWF and ultra large VWF multimers may aid in diagnosis of iTTP and help monitoring of disease processes following therapy. Our ongoing study is to determine whether these biomarkers can be used to predict responses to treatment and long-term outcome. Disclosures Zheng: Alexion: Research Funding, Speakers Bureau.

Decreased Plasma Tissue Factor Pathway Inhibitor Levels in Patients with Thrombotic Thrombocytopenic Purpura

1995 ◽  
Vol 73 (01) ◽  
pp. 010-014 ◽  
Author(s):  
Hideo Wada ◽  
Masayuki Kobayashi ◽  
Yoshihiro Wakita ◽  
Minori Shimura ◽  
Tutomu Nakase ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Healthy Volunteers ◽  
Tissue Factor ◽  
Thrombotic Thrombocytopenic Purpura ◽  
Plasma Levels ◽  
Tissue Factor Pathway Inhibitor ◽  
Vascular Endothelial Cell ◽  
Vascular Endothelial ◽  
Thrombocytopenic Purpura ◽  
Tissue Factor Pathway

SummaryWe measured plasma levels of tissue factor (TF) and tissue factor pathway inhibitor (TFPI) in patients with thrombotic thrombocytopenic purpura (TTP) and disseminated intravascular coagulation (DIC) to examine the relationship between TFPI and vascular endothelial cell injury. TF antigen was detected in the plasma of healthy volunteers, and the levels were significantly increased in the patients with DIC, but decreased slightly in those with TTP. Plasma TFPI levels were significantly decreased in patients with TTP compared with those in healthy volunteers. The concentration of plasma thrombomodulin (TM) antigen was significantly higher in those with TTP than in normal volunteers. One month after treatment, TTP patients showed a significant decrease in plasma TM levels, and a significant increase, in plasma TFPI levels, but plasma levels of TF antigen were not significantly increased. As plasma TFPI/TF ratio was significantly increased after treatment, the hypercoagulable state was therefore improved after treatment. There was no significant difference in plasma TF and TFPI levels between those who achieved complete remission (CR) and those who died. However, plasma TM levels were significantly higher in those who died than in those who achieved CR. Plasma TFPI levels might reflect injury of vascular endothelial cells as do plasma TM levels, and decreased plasma TFPI/TF ratio and vascular endothelial cell injuries might play causative roles in TTP.

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