Circulating Plasminogen Concentration at Admission in Patients with Coronavirus Disease 2019 (COVID-19)

Henry, Brandon Michael; Benoit, Stefanie; Hoehn, Jonathan; Lippi, Giuseppe; Favaloro, Emmanuel J.; Benoit, Justin L.

doi:10.1055/s-0040-1715454

Cited by 28 publications

(24 citation statements)

References 25 publications

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“…25 C3a/C3 was inversely correlated with plasminogen, in agreement with reports of lower plasminogen levels in COVID-19 patients requiring ICU admission, and thus suggesting fibrinolytic system disruption occurring in concert with complement hyperactivation. 26 Fibrinolysis disturbance due to increased PAI-1, 1 however, did not appear to be linked to complement hyperactivity, therefore suggesting that plasminogen depletion may be the result of consumptive fibrinolysis. 28 This association may explain in part the high complement levels observed in COVID-19 patients, given that the microthrombotic process triggered by ADAMTS13 deficiency has been shown to activate complement.…”

Section: Discussionmentioning

confidence: 96%

Complement levels at admission as a reflection of coronavirus disease 2019 (COVID‐19) severity state

Henry

Szergyuk

Oliveira

et al. 2021

Journal of Medical Virology

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Complement system hyperactivation has been proposed as a potential driver of adverse outcomes in severe acute respiratory syndrome coronavirus 2 infected patients, given prior research of complement deposits found in tissue and blood samples, as well as evidence of clinical improvement with anticomplement therapy. Its role in augmenting thrombotic microangiopathy mediated organ damage has also been implicated in coronavirus disease 2019 (COVID‐19). This study aimed to examine associations between complement parameters and progression to severe COVID‐19 illness, as well as correlations with other systems. Blood samples of COVID‐19 patients presenting to the emergency department (ED) were analyzed for a wide panel of complement and inflammatory biomarkers. The primary outcome was COVID‐19 severity at index ED visit, while the secondary outcome was peak disease severity over the course of illness. Fifty‐two COVID‐19 patients were enrolled. C3a ( p = 0.018), C3a/C3 ratio ( p = 0.002), and sC5b‐9/C3 ratio ( p = 0.021) were significantly elevated in with severe disease at ED presentation. Over the course of illness, C3a ( p = 0.028) and C3a/C3 ratio ( p = 0.003) were highest in the moderate severity group. In multivariate regression controlled for confounders, complement hyperactivation failed to predict progression to severe disease. C3a, C3a/C3 ratio, and sC5b‐9/C3 ratio were correlated positively with numerous inflammatory biomarkers, fibrinogen, and VWF:Ag, and negatively with plasminogen and ADAMTS13 activity. We found evidence of complement hyperactivation in COVID‐19, associated with hyperinflammation and thrombotic microangiopathy. Complement inhibition should be further investigated for potential benefit in patients displaying a hyperinflammatory and microangiopathic phenotype.

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Section: Discussionmentioning

confidence: 96%

Complement levels at admission as a reflection of coronavirus disease 2019 (COVID‐19) severity state

Henry

Szergyuk

Oliveira

et al. 2021

Journal of Medical Virology

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“…This is supported by the "fibrinolysis resistance" or "fibrinolysis shutdown" in vitro whole blood clot lysis 22,69,70 . The moderate reduction in circulating plasminogen of ICU COVID-19 patients eliminates the thrombolytic effects of tPA 71 , which is supported by thromboelastometry (TEM) 49,72 . As the half-life of plasminogen is 2.2 days, the fibrinolysis resistance in vitro cannot be explained by the distance to the clots in vivo (about 45 seconds per cycle through the circulation system) and the time between collection of blood to assay.…”

Section: Clinicopathological Mechanisms Of Fibrinolysis In Covid-19mentioning

confidence: 89%

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Zhao

et al. 2020

Preprint

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Background How aberrant fibrinolysis influences the clinical progression of COVID-19 presents a clinicopathological dilemma challenging intensivists. To investigate whether abnormal fibrinolysis is a culprit or protector or both, we associated elevated plasma D-dimer with clinical variables to identify a panoramic view of the derangements of fibrinolysis that contribute to the pathogenesis of COVID-19 based on studies available in the literature. Methods We performed this systematic review based on both meta-analysis and meta-regression to compute the correlation of D-dimer at admission with clinical features of COVID-19 patients in retrospective studies or case series. We searched the databases until Aug 18, 2020, with no limitations by language. The first hits were screened, data extracted, and analyzed in duplicate. We did the random-effects meta-analyses and meta-regressions (both univariate and multivariate). D-dimer associated clinical variables and potential mechanisms were schematically reasoned and graphed. Findings Our search identified 42 observational, or retrospective, or case series from six countries (n=14,862 patients) with all races and ages from 1 to 98-year-old. The weighted mean difference of D-dimer was 0.97 μg/mL (95% CI 0.65, 1.29) between relatively mild (or healthy control) and severely affected groups with significant publication bias. Univariate meta-regression identified 58 of 106 clinical variables were associated with plasma D-dimer levels, including 3 demographics, 5 comorbidies, 22 laboratory tests, 18 organ injury biomarkers, 8 severe complications, and 2 outcomes (discharge and death). Of these, 11 readouts were negatively associated with the level of plasma D-dimer. Further, age and gender were confounding factors for the identified D-dimer associated variables. There were 22 variables independently correlated with the D-dimer level, including respiratory rate, dyspnea plasma K+, glucose, SpO2, BUN, bilirubin, ALT, AST, systolic blood pressure, and CK. We thus propose that "insufficient hyperfibrinolysis (fibrinolysis is accelerated but unable to prevent adverse clinical impact for clinical deterioration COVID-19)" as a peculiar mechanism. Interpretation The findings of this meta-analysis- and meta-regression-based systematic review supports elevated D-dimer as an independent predictor for mortality and severe complications. D-dimer-associated clinical variables draw a landscape integrating the aggregate effects of systemically suppressive and locally (i.e., in the lung) hyperactive derangements of fibrinolysis. D-dimer and associated clinical biomarkers and conceptually parameters could be combined for risk stratification, potentially for tracking thrombolytic therapy or alternative interventions.

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“…This discrepancy can, however, be attributed to temporal changes in levels of tPA and PAI-1, as well as to insufficient hyperfibrinolysis characterized by systemic suppression and local (i.e., within the pulmonary tissue) hyperactive fibrinolysis derangement, as recently pinpointed by Ji et al 23 This is in concordance with recent observations by Henry et al where COVID-19 patients progressing to severe disease had lower levels of plasminogen compared with discharged patients. 12 This suggests that the high D-dimer levels observed in patients with severe COVID-19 may come from an initial rise in tPA/plasmin. This hypothesis is further supported by observations by Wright and colleagues where patients who met the criteria of hypofibrinolysis based on thromboelastographic findings had a marked decline in D-dimer levels after an initial rise.…”

mentioning

confidence: 99%

“…11 Henry and colleagues recently demonstrated that ICU-admitted COVID-19 patients had lower levels of circulating plasminogen than non-ICU patients, suggesting an exhaustion of fibrinolysis. 12 Recent small clinical studies have also demonstrated potential therapeutic effects of supplementing the fibrinolytic system, where exogenous administration of tissue plasminogen activator (tPA) resulted in improvement of respiratory function and reduced mortality in critically ill COVID-19 patients with acute respiratory distress syndrome (ARDS). 13,14 Herein, we performed a prospective observational study to determine whether circulating plasma levels of plasminogen activator inhibitor-1 (PAI-1) and tPA may be significantly elevated in patients with severe COVID-19.…”

mentioning

confidence: 99%

Circulating Levels of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 Are Independent Predictors of Coronavirus Disease 2019 Severity: A Prospective, Observational Study

Henry

Cheruiyot

Benoit

et al. 2021

Semin Thromb Hemost

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Circulating Plasminogen Concentration at Admission in Patients with Coronavirus Disease 2019 (COVID-19)

Abstract: Letter to the Editor 859 This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.

Cited by 28 publications

References 25 publications

Complement levels at admission as a reflection of coronavirus disease 2019 (COVID‐19) severity state

Complement levels at admission as a reflection of coronavirus disease 2019 (COVID‐19) severity state

Insufficient fibrinolysis in COVID-19: a systematic review of thrombolysis based on meta-analysis and meta-regression

Circulating Levels of Tissue Plasminogen Activator and Plasminogen Activator Inhibitor-1 Are Independent Predictors of Coronavirus Disease 2019 Severity: A Prospective, Observational Study

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