scholarly journals Increase in Ischemia-Modified Albumin and Pregnancy-Associated Plasma Protein-A in COVID-19 Patients

2021 ◽  
Vol 10 (23) ◽  
pp. 5474
Author(s):  
Belén G. Sanchez ◽  
Jose M. Gasalla ◽  
Manuel Sánchez-Chapado ◽  
Alicia Bort ◽  
Inés Diaz-Laviada
Keyword(s):  
Plasma Protein ◽  
Roc Curve ◽  
Troponin T ◽  
Early Stage ◽  
Acute Infection ◽  
Protein A ◽  
Early Infection ◽  
Serum Samples ◽  
Ischemia Modified Albumin ◽  
Control Subjects

This study was undertaken due to the urgent need to explore reliable biomarkers for early SARS-CoV-2 infection. We performed a retrospective study analyzing the serum levels of the cardiovascular biomarkers IL-6, TNF-α, N-terminal pro-B natriuretic peptide, cardiac troponin T (cTnT), ischemia-modified albumin (IMA) and pregnancy-associated plasma protein-A (PAPP-A) in 84 patients with COVID-19.Patients were divided into three groups according to their RT-qPCR and IgG values: acute infection (n = 35), early infection (n = 25) or control subjects (n = 24). Levels of biomarkers were analyzed in patient serum samples using commercially available ELISA kits. Results showed a significant increase in IMA and PAPP-A levels in the early infected patients. Moreover, multivariate analysis and receiver operating characteristic (ROC) curve showed that IMA and PAPP-A had excellent discrimination value for the early stage of COVID-19. For IMA, the area under the ROC curve (AUC) had a value of 0.94 (95% confidence interval (CI): 0.881–0.999). Likewise, the serum level of PAPP-A was significantly higher in patients with early infection than in the control subjects (AUC = 0.801 (95% CI: 0.673–0.929)). The combined use of IMA and PAPP-A enhanced the sensitivity for total SARS-CoV-2-infected patients to 93%. These results suggest that the increased levels of PAPP-A and IMA shed light on underlying mechanisms of COVID-19 physiopathology and might be used as efficient biomarkers with high sensitivity and specificity for the early stage of COVID-19. Importantly, when monitoring pregnancy and cardiovascular diseases using PAPP-A or IMA levels, a SARS-CoV-2 infection should be discarded for proper interpretation of the results.

scholarly journals Potential Use of Pregnancy-associated Plasma Protein-A and IMA as Biomarkers for the Early Stage of COVID-19

2021 ◽  
Author(s):  
Belén G Sánchez ◽  
Jose M Gasalla ◽  
Manuel Sanchez-Chapado ◽  
Alicia Bort ◽  
Ines Diaz-Laviada
Keyword(s):  
Plasma Protein ◽  
Roc Curve ◽  
Troponin T ◽  
Early Stage ◽  
Acute Infection ◽  
Protein A ◽  
Serum Levels ◽  
Early Infection ◽  
Control Group ◽  
Serum Samples

Abstract BackgroundThis study has been undertaken with the urgent need for exploring reliable biomarkers for early infection of SARS-CoV-2. We performed a retrospective study analyzing the serum levels of the cardiovascular biomarkers N-terminal pro-B natriuretic peptide (NT-proBNP), cardiac troponin T (cTnT), Ischemia Modified Albumin (IMA) and pregnancy associated plasma protein A (PAPP-A), in 84 patients with COVID-19. MethodsPatients were divided in three groups according to their RT-qPCR and IgG values in acute infection (n=35), early infection (n=25) or control subjects (n=24). Levels of biomarkers were analyzed in patient’s serum samples by commercially available ELISA kits.ResultsMultivariate analysis and Receiver Operating Characteristic (ROC) curve showed that IMA and PAPP-A, had an excellent discrimination value for the early stage of COVID-19. Serum levels of IMA in early SARS-CoV-2 infected patients were significantly higher than in the control group with an area under the ROC curve (AUC) value of 0.94 (95% confidence interval (CI): 0.881- 0.999). Likewise, the serum level of PAPP-A was significantly higher in patients with early infection than in controls [AUC = 0.801 (95% CI: 0.673–0.929)]. The combined use of IMA and PAPP-A enhanced the sensitivity for total SARS-CoV-2 infected patients to 93%. ConclusionsThese results suggest that the levels of PAPP-A and IMA might be used as efficient biomarkers for the early stage of COVID-19 with high sensitivity and specificity. Importantly, when monitoring pregnancy and cardiovascular diseases by PAPP-A or IMA levels, an infection by SARS-CoV-2 should be discarded for proper interpretation of the results.

scholarly journals Quantification of Proteolytically Active Pregnancy-Associated Plasma Protein-A with an Assay Based on Quenched Fluorescence

2007 ◽  
Vol 53 (5) ◽  
pp. 947-954 ◽  
Author(s):  
Claus Gyrup ◽  
Michael Christiansen ◽  
Claus Oxvig
Keyword(s):  
Proteolytic Activity ◽  
Plasma Protein ◽  
Basic Protein ◽  
Biological Function ◽  
Limit Of Detection ◽  
Protein A ◽  
Maternal Serum ◽  
Serum Samples ◽  
A Subunit ◽  
Eosinophil Major Basic Protein

Abstract Background: Maternal serum concentrations of pregnancy-associated plasma protein-A (PAPP-A, pappalysin-1, EC 3.4.24.79) are used to predict the occurrence of Down syndrome. In pregnancy, PAPP-A primarily circulates as a covalent 2:2 complex with the proform of eosinophil major basic protein (proMBP), which inhibits the proteolytic activity of PAPP-A. At term, however, ∼1% of PAPP-A exists as an active, uncomplexed dimer with proteolytic activity directed specifically toward insulin-like growth factor binding protein (IGFBP)-4 and IGFBP-5. No assays have been developed that allow quantification of PAPP-A proteolytic activity. Methods: We developed a sensitive and specific immunocapture assay for PAPP-A activity based on intramolecular quenched fluorescence. We used a 26-residue synthetic peptide derived from IGFBP-4 in which specific positions on each side of the PAPP-A cleavage site were substituted with 3-nitrotyrosine and o-aminobenzoic acid. Results: The assay detected the activity of recombinant PAPP-A as well as PAPP-A in serum samples from pregnant women. The limit of detection (mean signal of blank plus 3 SD) of the active PAPP-A subunit was 13 pmol/L, and the intra- and interassay CVs were <10% and <15%, respectively. Interestingly, the fraction of active PAPP-A decreased gradually from week 7 to week 19 of pregnancy. Conclusions: This method allows the measurement of PAPP-A enzymatic activity and because of its specificity it is relevant to the study of the biological function of PAPP-A. The method may also be useful in the diagnosis of pregnancy disorders.

scholarly journals Molecular Distinction of Circulating Pregnancy-Associated Plasma Protein A in Myocardial Infarction and Pregnancy

2005 ◽  
Vol 51 (1) ◽  
pp. 75-83 ◽  
Author(s):  
Qiu-Ping Qin ◽  
Saara Kokkala ◽  
Juha Lund ◽  
Natalia Tamm ◽  
Liisa-Maria Voipio-Pulkki ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Pregnant Women ◽  
Molecular Mass ◽  
Plasma Protein ◽  
Specific Antibody ◽  
Protein A ◽  
Gel Filtration ◽  
Single Peak ◽  
Serum Samples ◽  
A Subunit

Abstract Background: In the blood of pregnant women, pregnancy-associated plasma protein A (PAPP-A) is present as a covalent complex with the proform of eosinophil major basic protein (proMBP). Recently, increased serum concentrations of PAPP-A have been found in acute coronary syndromes (ACS). The aim of this study was to investigate whether the circulating PAPP-A in ACS is the same as that in pregnancy. Methods: We developed two time-resolved immunofluorometric assays based on a relative epitope map constructed by the use of 17 monoclonal antibodies. One assay, which measured total PAPP-A, used two PAPP-A subunit-specific antibodies. The other assay, which measured PAPP-A/proMBP complex, used one proMBP subunit-specific antibody and one PAPP-A subunit-specific antibody. Serum samples from four patients with myocardial infarction (MI), three pregnant women in their first trimester, and one in her third trimester were fractionated by gel filtration on a Superose™ 6 precision column. The two assays were used to analyze fractions obtained by gel filtration as well as serum samples serially collected from four other MI patients. Results: Pregnancy-related PAPP-A was eluted as a single peak with a molecular mass of ∼700 kDa, whereas ACS-related PAPP-A was also eluted as a single peak but with a molecular mass of ∼530 kDa. Pregnancy-related PAPP-A was detected equally by the two assays, whereas increased ACS-related PAPP-A was detected only by the assay for total PAPP-A. Conclusions: Our results provide the first evidence that circulating ACS-related PAPP-A is different from circulating pregnancy-related PAPP-A in that it is not complexed with proMBP. These findings provide a solid foundation for the design of immunoassays to accurately measure atherosclerosis-associated plasma protein A in the circulation.

scholarly journals Immunofluorometric Point-of-Care Assays for the Detection of Acute Coronary Syndrome-Related Noncomplexed Pregnancy-Associated Plasma Protein A

2006 ◽  
Vol 52 (9) ◽  
pp. 1794-1801 ◽  
Author(s):  
Saara Wittfooth ◽  
Qiu-Ping Qin ◽  
Juha Lund ◽  
Ilkka Tierala ◽  
Kari Pulkki ◽  
...  
Keyword(s):  
Detection Limit ◽  
Plasma Protein ◽  
Specific Antibody ◽  
Point Of Care ◽  
Protein A ◽  
Serum Samples ◽  
Coronary Syndrome ◽  
A Subunit ◽  
The Difference ◽  
Eosinophil Major Basic Protein

Abstract Background: We recently reported that the pregnancy-associated plasma protein A (PAPP-A) form specifically related to acute coronary syndromes (ACS) is not complexed with the proform of eosinophil major basic protein (proMBP). The aim of this study was to develop rapid point-of-care immunoassays for the measurement of the noncomplexed PAPP-A. Methods: We developed immunofluorometric noncompetitive dry-reagent assays for total PAPP-A with 2 PAPP-A subunit-specific monoclonal antibodies and for PAPP-A/proMBP complex with 1 PAPP-A subunit-specific antibody and 1 proMBP subunit-specific antibody. The concentration of noncomplexed PAPP-A was determined as the difference of the results obtained with the 2 assays. Results: The assays were linear from 0.5 to 300 mIU/L. The analytical detection limit and functional detection limit (CV <20%) were 0.18 mIU/L and 0.27 mIU/L for total PAPP-A assay and 0.23 mIU/L and 0.70 mIU/L for PAPP-A/proMBP assay, respectively. The total assay imprecisions were <10%, and recoveries were 88%–107% for both assays. The mean difference (95% limits of agreement) between the new total PAPP-A assay and a previously reported total PAPP-A assay was −3.2% (−45.7% to 39.3%; n = 546; P = 0.0019). In serum samples from 159 non-ACS individuals, median concentrations (interquartile range) were 2.42 (1.14) mIU/L for total PAPP-A, 2.20 (1.18) mIU/L for PAPP-A/proMBP, and 0.18 (0.63) mIU/L for noncomplexed PAPP-A. Total PAPP-A and PAPP-A/proMBP, but not noncomplexed PAPP-A, correlated with age (r = 0.290, P = 0.0002; r = 0.230, P = 0.0035; r = 0.075, P = 0.3483, respectively). Conclusions: The new assays described revealed that noncomplexed PAPP-A is found only in negligible amounts in non-ACS samples.

Performance of free β-human chorionic gonadotrophin (free β-hCG) and pregnancy associated plasma protein-A (PAPP-A) analysis between Delfia Xpress and AutoDelfia systems in The Netherlands

2009 ◽  
Vol 47 (2) ◽  
Author(s):  
Ingeborg H. Linskens ◽  
Marieke Levitus ◽  
Anneke Frans ◽  
Peter C.J.I. Schielen ◽  
John M.G. van Vugt ◽  
...  
Keyword(s):  
The Netherlands ◽  
Plasma Protein ◽  
Screening Program ◽  
Medical Center ◽  
Protein A ◽  
First Trimester ◽  
Chorionic Gonadotrophin ◽  
Human Chorionic Gonadotrophin ◽  
Serum Samples ◽  
Β Hcg

Abstract: The VU University Medical Center (VUmc) was the first hospital in the Netherlands to introduce the Delfia Xpress for the analysis of free β-human chorionic gonadotrophin (β-hCG) and pregnancy associated plasma protein-A (PAPP-A) in the first trimester screening program for Down syndrome. Since then, others have implemented this system. In this study, we tested the equality of measurements for free β-hCG and PAPP-A between Delfia Xpress systems and one AutoDelfia system.: A total of 40 serum samples were aliquoted and stored at –20°C. Samples were analyzed by six Delfia Xpress systems and one AutoDelfia system over a time period of 2 years.: The relationships between free β-hCG and PAPP-A were excellent for the different Delfia Xpress systems (r>0.99, p<0.0001). For PAPP-A, the agreement between the main system at VUmc and five other systems was linear with slopes between 0.99 and 1.06. Similarly, agreement for free β-hCG was linear with slopes between 0.99 and 1.09. Likewise, agreement for PAPP-A and free β-hCG was excellent for the AutoDelfia vs. the main Delfia Xpress at the VUmc (r>0.99, p<0.0001). For both PAPP-A and free β-hCG, the relationships were linear with slopes of 1.08 and 1.07.: We demonstrate an excellent agreement for the analysis of PAPP-A and free β-hCG between Delfia Xpress systems and one AutoDelfia system.Clin Chem Lab Med 2009;47:222–6.

scholarly journals Diagnostic Test of Serum Pregnancy-Associated Plasma Protein-A Level as Biomarker for Early Diagnosis of Acute Myocardial Infarction

2020 ◽  
Vol 26 (3) ◽  
Author(s):  
Novida Dwi Astuti ◽  
JB. Suparyatmo ◽  
Amiroh Kurniati
Keyword(s):  
Early Diagnosis ◽  
Plasma Protein ◽  
Roc Curve ◽  
Protein A ◽  
Cardiac Biomarkers ◽  
Enzyme Linked Immunosorbent Assay ◽  
Roc Curve Analysis ◽  
Total Occlusion ◽  
Cross Sectional ◽  
Coronary Syndrome

Acute coronary syndrome is the primary cause of death from heart disease worldwide. This syndrome is caused by ruptured/eroded coronary atherosclerotic plaque, resulting in partial/total occlusion of thrombosis. It is necessary to find novel cardiac biomarkers for the identification of plaque progression before ischemic and myocardial necrosis events. Pregnancy Associated Plasma Protein-A (PAPP-A) is an atherosclerotic mediator proven to be a biomarker for plaque instability. This study aimed to determine the performance of serum PAPP-A as a biomarker for the early diagnosis of AMI. This research was an analytical observational study with a cross-sectional approach. Serum PAPP-A was measured using enzyme-linked immunosorbent assay in 82 new patients. They had ACS and were admitted to the emergency installation of Dr. Moewardi Hospital in Surakarta in August-September 2019. The subjects were grouped into the AMI group (NSTEMI and STEMI) consisting of 49(59.8%) subjects and non-AMI (UAP) group composed of 33(40.2%) subjects based on ACS diagnostic criteria of PERKI 2018. Receiver Operator Characteristic (ROC) curve analysis showed that PAPP-A was a good discriminator between AMI and non-AMI patients. The area under the curve was 0.968, 95% CI (0.932–1.004), with a sensitivity of 91.8% and specificity of 90.9% (p< 0.05). The cut-off value from the ROC curve was 2,526 ng/mL. Serum PAPP-A level has excellent performance as a biomarker for early diagnosis of AMI. It can also function as a screening instrument for the identification of UAP cases developing into AMI.

scholarly journals Immunoassays Developed for Pregnancy-Associated Plasma Protein-A (PAPP-A) in Pregnancy May Not Recognize PAPP-A in Acute Coronary Syndromes

2006 ◽  
Vol 52 (3) ◽  
pp. 398-404 ◽  
Author(s):  
Qiu-Ping Qin ◽  
Saara Kokkala ◽  
Juha Lund ◽  
Natalia Tamm ◽  
Xuezhong Qin ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Plasma Protein ◽  
Acute Coronary Syndromes ◽  
Protein A ◽  
Cardiac Events ◽  
Serum Samples ◽  
Time Resolved ◽  
Coronary Syndromes ◽  
The Individual ◽  
In Pregnancy

Abstract Background: Pregnancy-associated plasma protein-A (PAPP-A) concentrations are increased in the circulation of patients with acute coronary syndromes (ACS) and are associated with future adverse cardiac events. PAPP-A in ACS differs from PAPP-A in pregnancy in that PAPP-A in ACS is not complexed with the proform of eosinophil major basic protein (proMBP). We investigated the effect of antibody selection on the utility of PAPP-A assays for measurement of PAPP-A in pregnancy and/or ACS, and whether immunoassays for PAPP-A in pregnancy are suitable for PAPP-A in ACS. Methods: We constructed 2-site sandwich time-resolved immunofluorometric assays using 22 monoclonal antibodies raised against pregnancy serum PAPP-A. All antibodies were studied in pairs, with each antibody used as either capture or tracer. We compared the reactivity of each antibody combination with PAPP-A/proMBP complex derived from pregnancy sera or with uncomplexed PAPP-A extracted from atherosclerotic plaques. Recombinant human PAPP-A and proMBP were also used to determine the specificity of the antibodies. We confirmed all major findings with serum samples collected from patients with myocardial infarction. Results: Six monoclonal antibodies reacted with the proMBP subunit of the PAPP-A/proMBP complex. Epitopes of 3 proMBP-reactive antibodies largely overlapped, but were well separated from those of another group of 3 proMBP-reactive antibodies. Assays using any of the 6 proMBP-reactive antibodies failed to detect PAPP-A in ACS. In addition, some 2-site assays capable of detecting PAPP-A in pregnancy were almost incapable of detecting PAPP-A in ACS, although the individual epitopes remained detectable in PAPP-A in ACS. Conclusions: Immunoassays developed for PAPP-A in pregnancy may not be suitable for PAPP-A in ACS. Assays for PAPP-A in ACS should be based on careful antibody selection and subjected to extensive testing with clinical ACS samples.

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