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

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. BarrettZe Zheng

Research output: Contribution to journal › Article › peer-review

3 Scopus citations

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.

Original language	English
Article number	102164
Journal	Research and Practice in Thrombosis and Haemostasis
Volume	7
Issue number	6
DOIs	https://doi.org/10.1016/j.rpth.2023.102164
State	Published - Aug 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Funding

We are grateful to all medical and research professionals at the Froedtert & MCW Medical Center, the CAP accredited MCW Tissue Bank, Versiti Blood Research Institute in Milwaukee, Wisconsin, and New York University Langone Health in New York for their dedication to caring for the patients, collecting samples, and generating the data included in this study. This study was funded by a COVID-19 Rapid Response Grant from the Cullen RunFoundation through the MCW Cardiovascular Center (to ZZ), a startup fund from the MCW and Versiti BRI (to ZZ), a Fellow Scholar Award and a Supplement Award from the American Society of Hematology (to ZZ and TJB), a Career Development Award from the American Heart Association (to ZZ, 19CDA34660043 and TJB 18CDA34110203AHA), R01HL163516 (to ZZ), R01HL167917 (to TJB), 20PRE35210461 (to WZ), NIH AI159536 (to WC), HL148120 (to RW), HL161127 (to RW), and R35HL144993 (to JSB). This research was, in part, funded by the National Institutes of Health (NIH) Agreement 1OT2HL156812 through the National Heart, Lung, and Blood Institute (NHLBI) CONNECTS program. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the NIH. The MCW Clinical Research Data Warehouse was supported by the NIH National Center for Advancing Translational Sciences (to Clinical & Translational Science Institute of Southeast Wisconsin, UL1TR001436). The CAP accredited MCW Tissue Bank COVID-19 Program was supported by the MCW department of Pathology, the MCW department of Medicine. Z.Y.Z. W.D. J.S.B. T.J.B. and Z.Z. designed the research. Z.Y.Z. W.D. W.Z. M.R. Y.X. T.J.B. and Y.C. performed the experiments and analyzed the data. M.Ro. H.L. E.A.S. M.Ra. and Z.Z. obtained the de-identified clinical research data and samples from MCW Tissue Bank COVID-19 Program. W.Z. M.B.G. S.J. D.W. W.C. and R.W. collected samples from the anti-SARS-CoV-2 plasma study. W.W. J.P.W. L.B.K. R.W. and R.L.S. provided critical advice related to study design and data interpretation. Z.Y.Z. W.D. T.J.B. and Z.Z. wrote the manuscript. All authors read and approved the final manuscript. JPW received grants from NHLBI (HL129193 [PI] and 1OT2 HL161847 [Site Co-I]), Pfizer, Inc (investigator-initiated grant [PI]), and Versiti Research Foundation (research grant Co-PI). SJ is a member of the American Society of Hematology. RLS received financial support from Medical College of Wisconsin, Versiti Blood Research Foundation, NIH-NHLBI, royalties from licensing a monoclonal antibody (unrelated to this manuscript) from Cornell University Research Foundation, consultant fees from ONA Pharmaceuticals for their program targeting CD36 for cancer therapeutics (not related to this manuscript), and honoraria from academic institutions. There are no competing interests to disclose. RLS was the past president and member of executive committee of American Society of Hematology. JB received consultant fees for Janssen and Amgen (2017-2019). There are no other competing interests to disclose. JPW received grants from NHLBI (HL129193 [ PI ] and 1OT2 HL161847 [Site Co-I]), Pfizer , Inc (investigator-initiated grant [ PI ]), and Versiti Research Foundation (research grant Co- PI ). SJ is a member of the American Society of Hematology. RLS received financial support from Medical College of Wisconsin , Versiti Blood Research Foundation, NIH- NHLBI , royalties from licensing a monoclonal antibody (unrelated to this manuscript) from Cornell University Research Foundation, consultant fees from ONA Pharmaceuticals for their program targeting CD36 for cancer therapeutics (not related to this manuscript), and honoraria from academic institutions. There are no competing interests to disclose. RLS was the past president and member of executive committee of American Society of Hematology. JB received consultant fees for Janssen and Amgen (2017-2019). There are no other competing interests to disclose. This study was funded by a COVID-19 Rapid Response Grant from the Cullen Run Foundation through the MCW Cardiovascular Center (to ZZ), a startup fund from the MCW and Versiti BRI (to ZZ), a Fellow Scholar Award and a Supplement Award from the American Society of Hematology (to ZZ and TJB), a Career Development Award from the American Heart Association (to ZZ, 19CDA34660043 and TJB 18CDA34110203AHA), R01HL163516 (to ZZ), R01HL167917 (to TJB), 20PRE35210461 (to WZ), NIH AI159536 (to WC ), HL148120 (to RW), HL161127 (to RW), and R35HL144993 (to JSB). This research was, in part, funded by the National Institutes of Health ( NIH ) Agreement 1OT2HL156812 through the National Heart, Lung, and Blood Institute ( NHLBI ) CONNECTS program. The views and conclusions contained in this document are those of the authors and should not be interpreted as representing the official policies, either expressed or implied, of the NIH. The MCW Clinical Research Data Warehouse was supported by the NIH National Center for Advancing Translational Sciences (to Clinical & Translational Science Institute of Southeast Wisconsin, UL1TR001436). The CAP accredited MCW Tissue Bank COVID-19 Program was supported by the MCW department of Pathology, the MCW department of Medicine.

Funders	Funder number
Cornell University Research Foundation
Cullen Run Foundation
DECA/NHLBI/NIH
New York University Langone Health
Translational Science Institute of Southeast Wisconsin	UL1TR001436
Versiti BRI
Versiti Blood Research Institute Foundation
Versiti Blood Research Institute in Milwaukee
Versiti Blood Research Institute Foundation
National Institutes of Health (NIH)	R35HL144993, HL161127, HL148120, 1OT2HL156812, AI159536
National Heart, Lung, and Blood Institute (NHLBI)	HL129193, 1OT2 HL161847
American Heart Association	20PRE35210461, TJB 18CDA34110203AHA, R01HL167917, 19CDA34660043, R01HL163516
Cullen Run Foundation
American Society of Hematology
Pfizer
National Center for Advancing Translational Sciences (NCATS)
Medical College of Wisconsin
Department of Medicine, Georgetown University
Department of Pathology, Northwestern University

Keywords

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

ASJC Scopus subject areas

Hematology

Access to Document

10.1016/j.rpth.2023.102164

Cite this

Zhang, Z., Dai, W., Zhu, W., Rodriguez, M., Lund, H., Xia, Y., Chen, Y., Rau, M., Schneider, E. A., Graham, M. B., Jobe, S., Wang, D., Cui, W., Wen, R., Whiteheart, S. W., Wood, J. P., Silverstein, R., Berger, J. S., Kreuziger, L. B., ... Zheng, Z. (2023). Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19. Research and Practice in Thrombosis and Haemostasis, 7(6), Article 102164. https://doi.org/10.1016/j.rpth.2023.102164

@article{00f41acfd704460dab32a0a357610fa3,

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

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",

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

note = "Publisher Copyright: {\textcopyright} 2023 The Author(s)",

year = "2023",

month = aug,

doi = "10.1016/j.rpth.2023.102164",

language = "English",

volume = "7",

number = "6",

}

Zhang, Z, Dai, W, Zhu, W, Rodriguez, M, Lund, H, Xia, Y, Chen, Y, Rau, M, Schneider, EA, Graham, MB, Jobe, S, Wang, D, Cui, W, Wen, R, Whiteheart, SW , Wood, JP, Silverstein, R, Berger, JS, Kreuziger, LB, Barrett, TJ & Zheng, Z 2023, 'Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19', Research and Practice in Thrombosis and Haemostasis, vol. 7, no. 6, 102164. https://doi.org/10.1016/j.rpth.2023.102164

TY - JOUR

T1 - Plasma tissue-type plasminogen activator is associated with lipoprotein(a) and clinical outcomes in hospitalized patients with COVID-19

AU - Zhang, Ziyu

AU - Dai, Wen

AU - Zhu, Wen

AU - Rodriguez, Maya

AU - Lund, Hayley

AU - Xia, Yuhe

AU - Chen, Yiliang

AU - Rau, Mary

AU - Schneider, Ellen Anje

AU - Graham, Mary Beth

AU - Jobe, Shawn

AU - Wang, Demin

AU - Cui, Weiguo

AU - Wen, Renren

AU - Whiteheart, Sidney W.

AU - Wood, Jeremy P.

AU - Silverstein, Roy

AU - Berger, Jeffery S.

AU - Kreuziger, Lisa Baumann

AU - Barrett, Tessa J.

AU - Zheng, Ze

PY - 2023/8

Y1 - 2023/8

N2 - 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.

AB - 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.

KW - COVID-19

KW - Plasminogen Activator

KW - SARS-CoV-2

KW - apoprotein(a)

KW - lipoprotein(a)

KW - thrombosis

KW - tissue plasminogen activator

UR - http://www.scopus.com/inward/record.url?scp=85169507694&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85169507694&partnerID=8YFLogxK

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DO - 10.1016/j.rpth.2023.102164

M3 - Article

AN - SCOPUS:85169507694

VL - 7

JO - Research and Practice in Thrombosis and Haemostasis

JF - Research and Practice in Thrombosis and Haemostasis

IS - 6

M1 - 102164

ER -

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

Abstract

Bibliographical note

Funding

Keywords

ASJC Scopus subject areas

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