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Research ArticleArticle

Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis

Jelena Colic, Iva Pruner, Nemanja Damjanov, Tatjana Pekmezovic, Mirjana Sefik-Bukilica and Aleksandra Antovic
The Journal of Rheumatology February 2022, jrheum.210931; DOI: https://doi.org/10.3899/jrheum.210931
Jelena Colic
J. Colic, MD, PhDc, Institute of Rheumatology, Belgrade, Serbia; I. Pruner, PhD, Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; N. Damjanov, MD, PhD, M. Sefik-Bukilica, MD, PhD, Institute of Rheumatology, Belgrade, Serbia School of Medicine University of Belgrade, Belgrade, Serbia; T. Pekmezovic, MD, PhD, Institute of Epidemiology, School of Medicine University of Belgrade, Belgrade, Serbia; A. Antovic, MD, PhD, Karolinska Institutet, Department of Medicine Division Solna of Rheumatology, Karolinska University Hospital, Rheumatology, Stockholm, Sweden. M. Sefik-Bukilica and A. Antovic contributed equally to this work. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. J. Colic, Institute of Rheumatology, Resavska 69 street, Belgrade, Serbia. Email: jcolicster@gmail.com. Accepted for publication February 2, 2022.
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Iva Pruner
J. Colic, MD, PhDc, Institute of Rheumatology, Belgrade, Serbia; I. Pruner, PhD, Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; N. Damjanov, MD, PhD, M. Sefik-Bukilica, MD, PhD, Institute of Rheumatology, Belgrade, Serbia School of Medicine University of Belgrade, Belgrade, Serbia; T. Pekmezovic, MD, PhD, Institute of Epidemiology, School of Medicine University of Belgrade, Belgrade, Serbia; A. Antovic, MD, PhD, Karolinska Institutet, Department of Medicine Division Solna of Rheumatology, Karolinska University Hospital, Rheumatology, Stockholm, Sweden. M. Sefik-Bukilica and A. Antovic contributed equally to this work. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. J. Colic, Institute of Rheumatology, Resavska 69 street, Belgrade, Serbia. Email: jcolicster@gmail.com. Accepted for publication February 2, 2022.
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Nemanja Damjanov
J. Colic, MD, PhDc, Institute of Rheumatology, Belgrade, Serbia; I. Pruner, PhD, Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; N. Damjanov, MD, PhD, M. Sefik-Bukilica, MD, PhD, Institute of Rheumatology, Belgrade, Serbia School of Medicine University of Belgrade, Belgrade, Serbia; T. Pekmezovic, MD, PhD, Institute of Epidemiology, School of Medicine University of Belgrade, Belgrade, Serbia; A. Antovic, MD, PhD, Karolinska Institutet, Department of Medicine Division Solna of Rheumatology, Karolinska University Hospital, Rheumatology, Stockholm, Sweden. M. Sefik-Bukilica and A. Antovic contributed equally to this work. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. J. Colic, Institute of Rheumatology, Resavska 69 street, Belgrade, Serbia. Email: jcolicster@gmail.com. Accepted for publication February 2, 2022.
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Tatjana Pekmezovic
J. Colic, MD, PhDc, Institute of Rheumatology, Belgrade, Serbia; I. Pruner, PhD, Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; N. Damjanov, MD, PhD, M. Sefik-Bukilica, MD, PhD, Institute of Rheumatology, Belgrade, Serbia School of Medicine University of Belgrade, Belgrade, Serbia; T. Pekmezovic, MD, PhD, Institute of Epidemiology, School of Medicine University of Belgrade, Belgrade, Serbia; A. Antovic, MD, PhD, Karolinska Institutet, Department of Medicine Division Solna of Rheumatology, Karolinska University Hospital, Rheumatology, Stockholm, Sweden. M. Sefik-Bukilica and A. Antovic contributed equally to this work. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. J. Colic, Institute of Rheumatology, Resavska 69 street, Belgrade, Serbia. Email: jcolicster@gmail.com. Accepted for publication February 2, 2022.
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Mirjana Sefik-Bukilica
J. Colic, MD, PhDc, Institute of Rheumatology, Belgrade, Serbia; I. Pruner, PhD, Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; N. Damjanov, MD, PhD, M. Sefik-Bukilica, MD, PhD, Institute of Rheumatology, Belgrade, Serbia School of Medicine University of Belgrade, Belgrade, Serbia; T. Pekmezovic, MD, PhD, Institute of Epidemiology, School of Medicine University of Belgrade, Belgrade, Serbia; A. Antovic, MD, PhD, Karolinska Institutet, Department of Medicine Division Solna of Rheumatology, Karolinska University Hospital, Rheumatology, Stockholm, Sweden. M. Sefik-Bukilica and A. Antovic contributed equally to this work. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. J. Colic, Institute of Rheumatology, Resavska 69 street, Belgrade, Serbia. Email: jcolicster@gmail.com. Accepted for publication February 2, 2022.
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Aleksandra Antovic
J. Colic, MD, PhDc, Institute of Rheumatology, Belgrade, Serbia; I. Pruner, PhD, Karolinska Institutet, Department of Molecular Medicine and Surgery, Stockholm, Sweden; N. Damjanov, MD, PhD, M. Sefik-Bukilica, MD, PhD, Institute of Rheumatology, Belgrade, Serbia School of Medicine University of Belgrade, Belgrade, Serbia; T. Pekmezovic, MD, PhD, Institute of Epidemiology, School of Medicine University of Belgrade, Belgrade, Serbia; A. Antovic, MD, PhD, Karolinska Institutet, Department of Medicine Division Solna of Rheumatology, Karolinska University Hospital, Rheumatology, Stockholm, Sweden. M. Sefik-Bukilica and A. Antovic contributed equally to this work. The authors declare no conflicts of interest relevant to this article. Address correspondence to Dr. J. Colic, Institute of Rheumatology, Resavska 69 street, Belgrade, Serbia. Email: jcolicster@gmail.com. Accepted for publication February 2, 2022.
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Abstract

Objective To assess thrombin generation, fibrin formation, and structure together with the fibrinolytic status in patients with systemic sclerosis (SSc) in relation to the occurrence of digital ulcers (DUs) during the course of disease.

Methods We studied variables of endothelial dysfunction, thrombin generation, overall hemostatic potential, and fibrin clot turbidity in plasma from 58 patients with SSc (39 with DU history and 19 DU-naïve) and 46 matched healthy controls (HCs). Fibrin structure was visualized using scanning electron microscopy (SEM). Finally, 39 patients with a history of DUs were followed for 1.5 years and the predictive value of all investigated markers for new DU onset was explored.

Results Significantly enhanced endogenous thrombin potential (ETP) and prolonged clot lysis time (CLT) were found in patients with DUs compared to HCs. CLT was prolonged in patients with DUs compared to those without, showing good validity in identifying DUs with an area under the curve of 0.7 (95% CI 0.6–0.8). The levels of ETP and intercellular adhesion molecule 1 were independently associated with CLT. Over the follow-up period, 20 patients developed new DUs. CLT was prolonged (P < 0.001) in patients with new DU episodes, especially those with recurrent DUs. Regression analysis showed that the Raynaud phenomenon visual analog scale and CLT were predictors of new DUs (OR 1.1, 95% CI 1.0–1.1 and OR 1.2, 95% CI 1.1–1.3, respectively). SEM confirmed denser fibrin clots in patients with new DUs.

Conclusion Our results suggest that impaired fibrinolysis might have an emerging role in underlying digital vasculopathy and its progression in SSc.

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The Journal of Rheumatology
Vol. 49, Issue 6
1 Jun 2022
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Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis
Jelena Colic, Iva Pruner, Nemanja Damjanov, Tatjana Pekmezovic, Mirjana Sefik-Bukilica, Aleksandra Antovic
The Journal of Rheumatology Feb 2022, jrheum.210931; DOI: 10.3899/jrheum.210931

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Impaired Fibrinolysis Is Linked With Digital Vasculopathy and Onset of New Digital Ulcers in Systemic Sclerosis
Jelena Colic, Iva Pruner, Nemanja Damjanov, Tatjana Pekmezovic, Mirjana Sefik-Bukilica, Aleksandra Antovic
The Journal of Rheumatology Feb 2022, jrheum.210931; DOI: 10.3899/jrheum.210931
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