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.

Figure 1

tPA enzymatic activity and Lp(a) concentration in 7 hospitalized non-COVID-19 patients and 20 hospitalized COVID-19 patients (cohort #1). (A) Plasma tPA enzymatic activity. The tPA enzymatic activity results are based on the enzymatic tPA activity of converting zymogen plasminogen to plasmin. (B) Plasma Lp(a) concentration. P values were calculated using two-tailed Student’s t test for tPA enzymatic activity result, and Mann-Whitney U test for Lp(a) result. Asterisks represent statistical significance at ∗P < .05 or ∗∗∗∗P < .0001. tPA, tissue-type plasminogen activator.

Figure 2

The longitudinal change of tPA enzymatic activity, Lp(a) concentration, d-dimer, and platelet count in 38 COVID-19 patients during hospitalization (cohort #2). All the 38 patients received one dose of convalescent plasma at day 0. Plasma samples were collected at day 7, 14 and 28 post convalescent plasma infusion. (A) tPA enzymatic activity from day 7 to day 28. Data were expressed as mean ± SD. (B) Lp(a) concentration from day 7 to day 28. Data were expressed as median ± interquartile range. (C) D-dimer were expressed as median ± interquartile range. (D) Platelet count was expressed as mean ± SD. P values were calculated using Paired t-test for comparing day 7 and day 28. Asterisks represent statistical significance at ∗P < .05 or ∗∗P < .01. tPA, tissue-type plasminogen activator.

Figure 3

The tPA enzymatic activity and Lp(a) concentration from plasma samples collected from 13 patients at onset of COVID-19 symptoms during hospitalization and after recovery from COVID-19 (cohort #1). (A) Plasma tPA enzymatic activity. (B) Plasma Lp(a) concentration. P values were calculated using two-tailed Student’s t test for tPA enzymatic activity result and Mann-Whitney U test for Lp(a) result. Asterisks represent statistical significance at ∗P < .05 or ∗∗P < .01. tPA, tissue-type plasminogen activator.

Figure 4

The inverse correlation between plasma tPA enzymatic activity and tPA concentration (cohort #1 and #2) in (A) all hospitalized patients including non-COVID-19 and COVID-19 patients. (B) Only COVID-19 patients. 27 subjects from cohort #1 (including 7 non-COVID-19 patients) and 38 subjects from cohort #2 were included in the analysis. Correlation analysis between tPA enzymatic activity and tPA concentration was performed by the Pearson correlation test. tPA, tissue-type plasminogen activator.