Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19

Ziyu Zhang; Wen Dai; Wen Zhu; Maya Rodriguez; Hayley Lund; Yuhe Xia; Yiliang Chen; Mary Rau; Ellen Anje Schneider; Mary Beth Graham; Shawn Jobe; Demin Wang; Weiguo Cui; Renren Wen; Sidney W Whiteheart; Jeremy P Wood; Roy Silverstein; Jeffery S Berger; Lisa Baumann Kreuziger; Tessa J Barrett; Ze Zheng

doi:10.1016/j.rpth.2023.102164

Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19

Res Pract Thromb Haemost. 2023 Aug 8;7(6):102164. doi: 10.1016/j.rpth.2023.102164. eCollection 2023 Aug.

Authors

Ziyu Zhang¹, Wen Dai¹, Wen Zhu^{1

2}, Maya Rodriguez^{1

3

4}, Hayley Lund⁵, Yuhe Xia⁶, Yiliang Chen^{1

5}, Mary Rau⁷, Ellen Anje Schneider⁷, Mary Beth Graham⁵, Shawn Jobe^{1

8}, Demin Wang¹, Weiguo Cui¹, Renren Wen¹, Sidney W Whiteheart^{9

10}, Jeremy P Wood^{9

10}, Roy Silverstein^{1

5}, Jeffery S Berger^{6

11}, Lisa Baumann Kreuziger^{1

5}, Tessa J Barrett⁶, Ze Zheng^{1

5}

Affiliations

¹ Versiti Blood Research Institute, Milwaukee, Wisconsin, USA.
² Department of Microbiology & Immunology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
³ Diversity Summer Health-Related Research Education Program (DSHREP), Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁴ College of Arts and Sciences, Marquette University, Milwaukee, Wisconsin, USA.
⁵ Department of Medicine, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁶ Department of Medicine, New York University Grossman School of Medicine, New York, New York, USA.
⁷ Department of Pathology, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.
⁸ Center for Bleeding and Clotting Disorders, Michigan State University, Lansing, Michigan, USA.
⁹ Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, USA.
¹⁰ Divison of Cardiovascular Medicine, Gill Heart and Vascular Institute, University of Kentucky, Lexington, Lexington, Kentucky, USA.
¹¹ Department of Surgery, New York University Langone Health, New York, New York, USA.

Abstract

Background: Patients with COVID-19 have a higher risk of thrombosis and thromboembolism, but the underlying mechanism(s) remain to be fully elucidated. In patients with COVID-19, high lipoprotein(a) (Lp(a)) is positively associated with the risk of ischemic heart disease. Lp(a), composed of an apoB-containing particle and apolipoprotein(a) (apo(a)), inhibits the key fibrinolytic enzyme, tissue-type plasminogen activator (tPA). However, whether the higher Lp(a) associates with lower tPA activity, the longitudinal changes of these parameters in hospitalized patients with COVID-19, and their correlation with clinical outcomes are unknown.

Objectives: To assess if Lp(a) associates with lower tPA activity in COVID-19 patients, and how in COVID-19 populations Lp(a) and tPA change post infection.

Methods: Endogenous tPA enzymatic activity, tPA or Lp(a) concentration were measured in plasma from hospitalized patients with and without COVID-19. The association between plasma tPA and adverse clinical outcomes was assessed.

Results: In hospitalized patients with COVID-19, we found lower tPA enzymatic activity and higher plasma Lp(a) than that in non-COVID-19 controls. During hospitalization, Lp(a) increased and tPA activity decreased, which associates with mortality. Among those who survived, Lp(a) decreased and tPA enzymatic activity increased during recovery. In patients with COVID-19, tPA activity is inversely correlated with tPA concentrations, thus, in another larger COVID-19 cohort, we utilized plasma tPA concentration as a surrogate to inversely reflect tPA activity. The tPA concentration was positively associated with death, disease severity, plasma inflammatory, and prothrombotic markers, and with length of hospitalization among those who were discharged.

Conclusion: High Lp(a) concentration provides a possible explanation for low endogenous tPA enzymatic activity, and poor clinical outcomes in patients with COVID-19.

Keywords: COVID-19; Plasminogen Activator; SARS-CoV-2; apoprotein(a); lipoprotein(a); thrombosis; tissue plasminogen activator.

Abstract

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