Elevated Lactate Levels in Acute Pulmonary Embolism Are Associated with Prothrombotic Fibrin Clot Properties: Contribution of NETs Formation

Abstract

Background: Elevated plasma lactate levels correlate with high mortality rate in acute pulmonary embolism (PE) patients. We hypothesized that elevated lactate levels correlate with prothrombotic fibrin clot properties and enhanced neutrophil extracellular trap (NET) formation in acute PE. Methods: As many as 126 normotensive acute PE patients (aged 58 ± 14 years) were enrolled. Plasma fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP), citrullinated histone H3 (citH3), and plasminogen activator inhibitor-1 antigen (PAI-1), together with plasma L-lactate levels were evaluated on admission. Results: Lactate levels ≥2 mM were found in 70 (55.6%) patients in whom we observed 29% higher neutrophil count and 45% elevated plasma citH3 levels. Elevated lactate levels were associated with more prothrombotic fibrin properties as reflected by 11% reduced Ks, 13% longer CLT, along with 11% increased ETP. Lactate levels were positively associated with plasma citH3 concentrations, ETP, CLT, and PAI-1 (p < 0.05). An increase of lactate levels by 1 mM leading to the prolongation of CLT by 8.82 min was shown in the linear regression. Conclusions: Our findings suggest a new mechanism contributing to a negative impact of elevated lactate levels on prognosis in acute PE patients, in particular hypofibrinolysis, associated with enhanced NET formation.

Impaired Fibrinolysis in Patients with Isolated Aortic Stenosis is Associated with Enhanced Oxidative Stress

“…This methodological difference might justify why oxidative stress has a crucial effect on impaired fibrinolysis in AS despite the various demographic and laboratory determinants of prolonged lysis time between these assays (Siudut et al manuscript in review). The assay by Pieters et al that was introduced in 2019 and supported by the International Society on Thrombosis and Hemostasis Subcommittee has been used in a few studies [ 23 , 25 , 26 ] and is known to be more sensitive to endogenous PAI-1 levels, especially in both hypofibrinolytic and/or hyperfibrinolytic conditions [ 27 ]. On the other hand, the Lys50 assay has been previously applied in studies investigating fibrinolytic capacity in patients with metabolic syndrome, including diabetes mellitus [ 24 ].…”

Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism

“…Such impaired fibrin clot phenotype was associated with increased thrombin formation, enhanced inflammatory state, and potentially oxidative modifications of coagulation proteins. As was previously shown in acute PE patients, increased thrombin generation, inflammation, NET generation reflected by increased levels of citrullinated histones H3, and hypoxia are factors, which unfavorably modulate fibrin clot properties [ 59 , 60 ], regardless of FXIII consumption. On the other hand, it has recently been shown in vitro by Vasilyeva et al [ 61 ] that purified human FXIII undergoes an extensive oxidation on methionine residues as a reactive oxygen species scavenger and protects other amino acids and/or proteins against oxidative modifications.…”

Fibrinolysis in Venous Thromboembolism

“…One of the mechanisms underlying this observation likely results from a positive association of CLT with blood lactate concentrations, a well-established marker of hypoxia and injury in acute PE, which negatively impacts early mortality. 51 It is still unknown whether these observations can be extrapolated to hemodynamically unstable acute PE patients in whom mortality risk is high.…”