Publications by authors named "C M Cobbaert"

186 Publications

Biochemical risk factors of atherosclerotic cardiovascular disease: from a narrow and controversial approach to an integral approach and precision medicine.

Expert Rev Cardiovasc Ther 2021 Dec 3;19(12):1085-1096. Epub 2022 Jan 3.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: Guidelines of management of dyslipidemias and prevention of cardiovascular disease (CVD) are based on firm scientific evidence obtained by randomized controlled trials (RCTs). However, the role of elevated low-density lipoprotein-cholesterol (LDL-C)as a risk factor of CVD and therapies to lower LDL-C are frequently disputed by colleagues who disagree with the conclusions of the RCTs published. This review focuses on this dispute, and evaluates the current approach of management of dyslipidemias and CVD prevention to find modern alternatives for more precise diagnosis and therapy of dyslipidemic patients.

Areas Covered: Recent interest in lipoprotein(a) (Lp(a)) and remnants lipoproteins and in therapies that do not influence LDL-C levels primarily, such as anti-inflammatory drugs and icosapent ethyl, has revitalized our concern to optimize the care for patients with increased CVD risk without focusing simply on reduction of LDL-C by therapy with statins, ezitemibe, and proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors.

Expert Opinion: The limited characterization of study populations by measurement of total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C) and triglycerides (TG) followed by measurement or calculation of LDL-C should be extended by a more integral approach in order to realize precision diagnostics and precision medicine, for the sake of personalized patient care.
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http://dx.doi.org/10.1080/14779072.2021.2022475DOI Listing
December 2021

Effect of the reaction temperature on the prothrombin time and the apparent International Normalized Ratio determined with International Standards for thromboplastins.

Int J Lab Hematol 2021 Nov 8. Epub 2021 Nov 8.

Coagulation Reference Laboratory, Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Introduction: The definition of the International Normalized Ratio (INR) depends on a reference measurement procedure for the prothrombin time (PT) determined with international standards for thromboplastins. The agreed water bath temperature for PT determination in the reference measurement procedure is 37°C. The aim of the study was to assess the influence of small deviations of the agreed reaction temperature on PT and INR determined with World Health Organization international standards for thromboplastins rTF/16 (recombinant human) and RBT/16 (rabbit brain).

Methods: Prothrombin time was determined, with a manual hook technique, in glass test tubes in a water bath at a controlled temperature. The PT reaction temperatures were varied between 28 and 40°C. Pooled normal plasma and pooled coumarin plasma (INR ≈ 2.8) were used as test plasmas. The data were fitted to a quadratic relationship between PT and temperature.

Results: Prothrombin times with rTF/16 were shortened by increasing the reaction temperature up to approximately 39-40°C. PTs with RBT/16 were shortened by increasing the reaction temperature up to approximately 34-37°C, but were prolonged at higher temperatures. The apparent INR change of the coumarin plasma at 37.0°C was 0.06/°C and 0.11/°C for rTF/16 and RBT/16, respectively.

Conclusions: Reaction temperature had a significant effect on PT and the apparent INR with the International Standards. At 37.0°C, the apparent INR of coumarin plasma determined with RBT/16 was more responsive to temperature change than the apparent INR determined with rTF/16. The required accuracy of the water bath temperature should be 37.0 ± 0.1°C.
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http://dx.doi.org/10.1111/ijlh.13737DOI Listing
November 2021

Development and Provisional Validation of a Multiplex LC-MRM-MS Test for Timely Kidney Injury Detection in Urine.

J Proteome Res 2021 Dec 4;20(12):5304-5314. Epub 2021 Nov 4.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands.

Kidney injury is a complication frequently encountered in hospitalized patients. Early detection of kidney injury prior to loss of renal function is an unmet clinical need that should be targeted by a protein-based biomarker panel. In this study, we aim to quantitate urinary kidney injury biomarkers at the picomolar to nanomolar level by liquid chromatography coupled to tandem mass spectrometry in multiple reaction monitoring mode (LC-MRM-MS). Proteins were immunocaptured from urinary samples, denatured, reduced, alkylated, and digested into peptides before LC-MRM-MS analysis. Stable-isotope-labeled peptides functioned as internal standards, and biomarker concentrations were attained by an external calibration strategy. The method was evaluated for selectivity, carryover, matrix effects, linearity, and imprecision. The LC-MRM-MS method enabled the quantitation of KIM-1, NGAL, TIMP2, IGFBP7, CXCL9, nephrin, and SLC22A2 and the detection of TGF-β1, cubilin, and uromodulin. Two to three peptides were included per protein, and three transitions were monitored per peptide for analytical selectivity. The analytical carryover was <1%, and minimal urine matrix effects were observed by combining immunocapture and targeted LC-MRM-MS analysis. The average total CV of all quantifier peptides was 26%. The linear measurement range was determined per measurand and found to be 0.05-30 nmol/L. The targeted MS-based method enables the multiplex quantitation of low-abundance urinary kidney injury biomarkers for future clinical evaluation.
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http://dx.doi.org/10.1021/acs.jproteome.1c00532DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8650098PMC
December 2021

Unraveling a borderline antithrombin deficiency case with quantitative mass spectrometry.

J Thromb Haemost 2022 Jan 26;20(1):145-148. Epub 2021 Oct 26.

Department of Clinical Chemistry and Laboratory Medicine, Leiden University Medical Center, Leiden, The Netherlands.

Antithrombin deficiency diagnostics by first-line activity tests suffer from a lack of sensitivity sometimes resulting in diagnostic uncertainty. We here present a case of a woman with recurrent pregnancy loss who was screened for inherited thrombophilia. Antithrombin activity was borderline low, resulting in uncertainty about the correct diagnosis. Using a mass spectrometry-based test, the antithrombin protein of the patient was characterized at the molecular level and a heterozygous p.Pro73Leu mutation was identified. The mutation, also known as antithrombin "Basel," increases the risk of venous thromboembolism and obstetric complications. This case is illustrative of current antithrombin deficiency screening, in which diagnoses may be missed by traditional diagnostics. Next-generation protein diagnostics by mass spectrometry provides molecular insight into the proteoforms present in vivo. This information is essential for laboratory specialists and clinicians to unambiguously diagnose patients and will aid in evolving healthcare from traditional to precision diagnostics.
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http://dx.doi.org/10.1111/jth.15553DOI Listing
January 2022

Implementation of the new EU IVD regulation - urgent initiatives are needed to avert impending crisis.

Clin Chem Lab Med 2021 Sep 15. Epub 2021 Sep 15.

Institute for Clinical Chemistry, Medical Faculty Mannheim of Heidelberg University, Mannheim, Germany.

Laboratory medicine in the European Union is at the dawn of a regulatory revolution as it reaches the end of the transition from IVDD 98/79/EC (https://eur-lex.eur-opa.eu/legal-content/EN/TXT/?uri=CELEX%3A31998L0079&qid=1628781352814) to IVDR 2017/746 https://eur-lex.europa.eu/eli/reg/2017/746. Without amendments and contingency plans, implementation of the IVDR in May 2022 will lead the healthcare sector into uncharted waters due to unpreparedness of the EU regulatory infrastructure. Prospective risk analyses were not made by the European Commission, and if nothing happens it can be anticipated that the consequences will impact all stakeholders of the medical test pipeline, may seriously harm patients and may prevent caregivers from making appropriate clinical decisions due to non-availability of medical tests. Finally, it also may discourage manufacturers and academia from developing specialty tests, thereby hampering innovation in medical diagnostic care. We hereby inform laboratory professionals about the imminent diagnostic collapse using testimonies from representative stakeholders of the diagnostic supply chain and from academia developing innovative in-house tests in domains of unmet clinical needs. Steps taken by the EFLM Task Force on European Regulatory Affairs, under the umbrella of the Biomedical Alliance in Europe, will be highlighted, as well as the search for solutions through dialogue with the European Commission. Although we recognize that the IVDR promotes positive goals such as increased clinical evidence, surveillance, and transparency, we need to ensure that the capabilities of the diagnostic sector are not damaged by infrastructural unpreparedness, while at the same time being forced to submit to a growing bureaucratic and unsupportive structure that will not support its "".
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http://dx.doi.org/10.1515/cclm-2021-0975DOI Listing
September 2021
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