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. 2022 Aug 19;10(8):2011.
doi: 10.3390/biomedicines10082011.

Biomarkers of Clot Activation and Degradation and Risk of Future Major Cardiovascular Events in Acute Exacerbation of COPD: A Cohort Sub-Study in a Randomized Trial Population

Peter Kamstrup  1 , Jannie Marie Bülow Sand  2 , Charlotte Suppli Ulrik  3   4 , Julie Janner  3 , Christian Philip Rønn  1 , Sarah Rank Rønnow  2 , Diana Julie Leeming  2 , Sidse Graff Jensen  1 , Torgny Wilcke  1   4 , Alexander G Mathioudakis  5   6 , Marc Miravitlles  7 , Therese Lapperre  8   9 , Elisabeth Bendstrup  10   11 , Ruth Frikke-Schmidt  4   12 , Daniel D Murray  13 , Theis Itenov  13 , Apostolos Bossios  14   15 , Susanne Dam Nielsen  4   16 , Jørgen Vestbo  5   6 , Tor Biering-Sørensen  17   18 , Morten Karsdal  2 , Jens-Ulrik Jensen  1   4   13 , Pradeesh Sivapalan  1
Affiliations

Biomarkers of Clot Activation and Degradation and Risk of Future Major Cardiovascular Events in Acute Exacerbation of COPD: A Cohort Sub-Study in a Randomized Trial Population

Peter Kamstrup et al. Biomedicines. .

Abstract

Cardiovascular diseases are common in patients with chronic obstructive pulmonary disease (COPD). Clot formation and resolution secondary to systemic inflammation may be a part of the explanation. The aim was to determine whether biomarkers of clot formation (products of von Willebrand Factor formation and activation) and clot resolution (product of fibrin degeneration) during COPD exacerbation predicted major cardiovascular events (MACE). The cohort was based on clinical data and biobank plasma samples from a trial including patients admitted with an acute exacerbation of COPD (CORTICO-COP). Neo-epitope biomarkers of formation and the activation of von Willebrand factor (VWF-N and V-WFA, respectively) and cross-linked fibrin degradation (X-FIB) were assessed using ELISAs in EDTA plasma at the time of acute admission, and analyzed for time-to-first MACE within 36 months, using multivariable Cox proportional hazards models. In total, 299/318 participants had samples available for analysis. The risk of MACE for patients in the upper quartile of each biomarker versus the lower quartile was: X-FIB: HR 0.98 (95% CI 0.65-1.48), VWF-N: HR 1.56 (95% CI 1.07-2.27), and VWF-A: HR 0.78 (95% CI 0.52-1.16). Thus, in COPD patients with an acute exacerbation, VWF-N was associated with future MACE and warrants further studies in a larger population.

Keywords: COPD exacerbation; biomarkers; coagulation; cross-linked fibrin degradation; major cardiovascular events; von Willebrand factor.

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Conflict of interest statement

Authors J.M.B.S., S.R.R., D.J.L. and M.K. are employees and shareholders of Nordic Bioscience. Outside the submitted work: C.S.U. has received grants from Sanofi, Boehringer Ingelheim, AstraZeneca and Novartis; speaker fees from Orion Pharma, AstraZeneca and TEVA; consulting fees from Chiesi, Orion Pharma, AstraZeneca, GSK and TEVA; and has been on advisory boards for Novartis, Sanofi, Glaxo-Smith Kline, Chiesi, AstraZeneca and Boehringer Ingelheim. M.M. has received a grant from Grifols and consulting fees from AstraZeneca, Atriva Therapeutics, Boehringer Ingelheim, Chiesi, GlaxoSmithKline, Bial, Gebro Pharma, CSL Behring, Laboratorios Esteve, Ferrer, Mereo Biopharma, Verona Pharma, Spin Therapeutics, pH Pharma, ONO Pharma, Palobiofarma SL, Takeda, Novartis, Sanofi and Grifols; speaker fees from AstraZeneca, GlaxoSmithKline, Boehringer Ingelheim, Chiesi, Cipla, Kamada, Takeda, Menarini, Rovi, Bial, Sandoz, Zambon, CSL Behring, Grifols and Novartis; support for attending meetings/travel from Novartis, Boehringer Ingelheim and Menarini; and participation on DSMB for Mereo. EB has received speaker fees from Boehringer Ingelheim and Chiesi, support for attending meetings/travel from Boehringer Ingelheim, and participation on DSMB or advisory board for Boehringer Ingelheim. AB is the secretary of Assembly 5, Airway diseases, Asthma, COPD and Chronic Cough; European Respiratory Society. J.V. has received a grant from Boehringer Ingelheim UK; consulting fees from AstraZeneca, ALK Abello, Boehringer Ingelheim, GSK, Novartis and TEVA; speaker fees from AstraZeneca, Boehringer Ingelheim, Chiesi, GSK and Novartis; and participation on DSMB/advisory boards for AstraZeneca and GSK. All other authors report no conflict of interest. TB-S received consulting fees from GSK and Sanofi Pasteur; received speaker payments from Bayer, Sanofi Pasteur and GSK; support for meetings/travel from AstraZeneca; and received equipment for his department from GE.

Figures

Figure 1
Figure 1
Study flowchart.
Figure 2
Figure 2
Characteristics of biomarkers at baseline. X-FIB: Cross-linked fibrin degeneration. VWF-N: N-terminal of von Willebrand Factor formation. VWF-A: Neoepitope of ADAMTS13-mediated activation of von Willebrand Factor. IQR: Interquartile range. MACE: Major cardiovascular event. *: For comparison between ‘MACE’ and ‘No MACE’ subgroups.
Figure 3
Figure 3
(A–C) Change in X-FIB (A), VWF-N (B), and VWF-A (C) from admission to follow-up. X-FIB: Cross-linked fibrin degeneration. VWF-N: N-terminal of von Willebrand Factor formation. VWF-A: Neoepitope of ADAMTS13-mediated activation of von Willebrand Factor. IQR: Interquartile range.
Figure 4
Figure 4
Forest plot showing the results of the multivariable Cox proportional hazards regression on risk of major cardiovascular events for X-FIB, VWF-N, and VWF-A; Hazard Ratio (95% confidence interval). Adjusted for age, sex, forced expiratory volume in one second (% of predicted), former ischemic heart disease, former heart failure, atrial fibrillation/flutter, hypertension, hypercholesterolemia, peripheral vascular disease type 2 diabetes, smoking status, and ICS use. °: X-FIB HR estimate, |: VWF-N HR estimate, ×: VWF-A HR estimate.
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