Reliable measurement of plasma kinin peptides: Importance of preanalytical variables

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Abstract

Background

The kallikrein‐kinin system is involved in many (patho)physiological processes and kinin peptides are considered potential clinical biomarkers. Variance in blood specimen collection and processing, artificial ex vivo bradykinin formation, and rapid degradation of kinins have contributed to divergence in published plasma levels, therefore limiting their significance. Thus, reliable preanalytical settings are highly required.

Objectives

This study aimed to develop and evaluate a standardized preanalytical procedure for reliable kinin quantification. The procedure was based on identification of the most impactful variables on ex vivo plasma level alterations.

Methods

Suitable protease inhibitors and blood specimen collection and handling conditions were systematically investigated. Their influence on plasma levels of seven kinins was monitored using an established in‐house liquid chromatography–tandem mass spectrometry platform.

Results

In nonstandardized settings, ex vivo rise of bradykinin was found to already occur 30 seconds after blood sampling with high interindividual variation. The screening of 17 protease inhibitors resulted in a customized seven‐component protease inhibitor, which efficiently stabilized ex vivo kinin levels. The reliability of kinin levels was substantially jeopardized by prolonged rest time until centrifugation, phlebotomy methodology (eg, straight needles, catheters), vacuum sampling technique, or any time delays during venipuncture. The subsequently developed standardized procedure was applied to healthy volunteers and proved it significantly limited interday and interindividual kinin level variability.

Conclusion

The developed procedure for blood specimen collection and handling is feasible in clinical settings and allows for determination of reliable kinin levels. It may contribute to further elucidating the role of the kallikrein‐kinin system in diseases like angioedema, sepsis, or coronavirus disease 2019.

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Most cited references 38

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A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

Michael R. Garvin, Christiane Alvarez, J Izaak Miller … (2020)

Neither the disease mechanism nor treatments for COVID-19 are currently known. Here, we present a novel molecular mechanism for COVID-19 that provides therapeutic intervention points that can be addressed with existing FDA-approved pharmaceuticals. The entry point for the virus is ACE2, which is a component of the counteracting hypotensive axis of RAS. Bradykinin is a potent part of the vasopressor system that induces hypotension and vasodilation and is degraded by ACE and enhanced by the angiotensin1-9 produced by ACE2. Here, we perform a new analysis on gene expression data from cells in bronchoalveolar lavage fluid (BALF) from COVID-19 patients that were used to sequence the virus. Comparison with BALF from controls identifies a critical imbalance in RAS represented by decreased expression of ACE in combination with increases in ACE2, renin, angiotensin, key RAS receptors, kinogen and many kallikrein enzymes that activate it, and both bradykinin receptors. This very atypical pattern of the RAS is predicted to elevate bradykinin levels in multiple tissues and systems that will likely cause increases in vascular dilation, vascular permeability and hypotension. These bradykinin-driven outcomes explain many of the symptoms being observed in COVID-19.

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Errors in a stat laboratory: types and frequencies 10 years later.

Mario Plebani, Paolo Carraro (2007)

In view of increasing attention focused on patient safety and the need to reduce laboratory errors, it is important that clinical laboratories collect statistics on error occurrence rates over the whole testing cycle, including pre-, intra-, and postanalytical phases. The present study was conducted in 2006 according to the design we previously used in 1996 to monitor the error rates for laboratory testing in 4 different departments (internal medicine, nephrology, surgery, and intensive care). For 3 months, physicians and nurses were asked to pay careful attention to all test results. Any suspected laboratory error was recorded with associated pertinent clinical information. Every day, a laboratory physician visited the 4 departments and a critical appraisal was made of any suspect results. Among a total of 51 746 analyses, clinicians notified us of 393 questionable findings, 160 of which were confirmed as laboratory errors. The overall frequency of errors, 3092 ppm, was significantly lower (P <0.05) than in 1996 (4700 ppm). Of the 160 confirmed errors, 61.9% were preanalytical errors, 15% were analytical, and 23.1% were postanalytical. During the last decade the error rates in our stat laboratory have been reduced significantly. As demonstrated by the distribution pattern, the pre- and postanalytical steps still have the highest error prevalences, but changes have occurred in the types and frequencies of errors in these phases of testing.

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Errors in laboratory medicine.

Mario Plebani, Pierangelo A. Bonini, Ferruccio Ceriotti … (2002)

The problem of medical errors has recently received a great deal of attention, which will probably increase. In this minireview, we focus on this issue in the fields of laboratory medicine and blood transfusion. We conducted several MEDLINE queries and searched the literature by hand. Searches were limited to the last 8 years to identify results that were not biased by obsolete technology. In addition, data on the frequency and type of preanalytical errors in our institution were collected. Our search revealed large heterogeneity in study designs and quality on this topic as well as relatively few available data and the lack of a shared definition of "laboratory error" (also referred to as "blunder", "mistake", "problem", or "defect"). Despite these limitations, there was considerable concordance on the distribution of errors throughout the laboratory working process: most occurred in the pre- or postanalytical phases, whereas a minority (13-32% according to the studies) occurred in the analytical portion. The reported frequency of errors was related to how they were identified: when a careful process analysis was performed, substantially more errors were discovered than when studies relied on complaints or report of near accidents. The large heterogeneity of literature on laboratory errors together with the prevalence of evidence that most errors occur in the preanalytical phase suggest the implementation of a more rigorous methodology for error detection and classification and the adoption of proper technologies for error reduction. Clinical audits should be used as a tool to detect errors caused by organizational problems outside the laboratory.

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Author and article information

Contributors

Bjoern B. Burckhardt:

ORCID: https://orcid.org/0000-0002-1782-9937

bjoern.burckhardt@hhu.de

Journal

Journal ID (nlm-ta): Res Pract Thromb Haemost

Journal ID (iso-abbrev): Res Pract Thromb Haemost

Journal ID (doi): 10.1002/(ISSN)2475-0379

Journal ID (publisher-id): RTH2

Title: Research and Practice in Thrombosis and Haemostasis

Publisher: John Wiley and Sons Inc. (Hoboken )

ISSN (Electronic): 2475-0379

Publication date (Electronic): 12 January 2022

Publication date Collection: January 2022

Volume: 6

Issue: 1 ( doiID: 10.1002/rth2.v6.1 )

Electronic Location Identifier: e12646

Affiliations

[ ¹ ] Institute of Clinical Pharmacy and Pharmacotherapy Heinrich‐Heine University Dusseldorf Germany

Author notes

[*] [* ] Correspondence

Bjoern B. Burckhardt, Heinrich‐Heine University, Institute of Clinical Pharmacy and Pharmacotherapy, Universitaetsstr. 1, 40225 Düsseldorf, Germany.

Email: bjoern.burckhardt@ 123456hhu.de

Author information

Bjoern B. Burckhardt https://orcid.org/0000-0002-1782-9937

Article

Publisher ID: RTH212646

DOI: 10.1002/rth2.12646

PMC ID: 8753134

PubMed ID: 35036825

SO-VID: 3c8a1734-89a7-4b7a-9b02-034a3d69b29d

License:

This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc-nd/4.0/ License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.

History

Date revision received : 12 November 2021

Date received : 01 August 2021

Date accepted : 18 November 2021

Page count

Figures: 7, Tables: 2, Pages: 12, Words: 6100

Custom metadata

source-schema-version-number 2.0

cover-date January 2022

details-of-publishers-convertor Converter:WILEY_ML3GV2_TO_JATSPMC version:6.7.0 mode:remove_FC converted:12.01.2022

Keywords: blood specimen collection,bradykinin,factor xii,kallikrein‐kinin system,phlebotomy

Data availability:

Keywords: blood specimen collection, bradykinin, factor xii, kallikrein‐kinin system, phlebotomy

Reliable measurement of plasma kinin peptides: Importance of preanalytical variables

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Abstract

Background

Objectives

Methods

Results

Conclusion

Related collections

Novel Coronavirus Disease COVID-19

Most cited references 38

A mechanistic model and therapeutic interventions for COVID-19 involving a RAS-mediated bradykinin storm

Errors in a stat laboratory: types and frequencies 10 years later.

Errors in laboratory medicine.

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