Prothrombotic fibrin clot properties associated with NETs formation characterize acute pulmonary embolism patients with higher mortality risk

Ząbczyk, Michał; Natorska, Joanna; Janion−Sadowska, Agnieszka; Metzgier-Gumiela, Agnieszka; Polak, Mateusz; Plens, Krzysztof; Janion, Marianna; Skonieczny, Grzegorz; Mizia-Stec, Katarzyna; Undas, Anetta

doi:10.1038/s41598-020-68375-7

Cited by 36 publications

(42 citation statements)

References 28 publications

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“…Recently, we have shown that prothrombotic fibrin clot phenotype, including reduced clot permeability and prolonged CLT, was associated with higher early mortality risk and enhanced neutrophil extracellular trap formation in acute PE patients. 14 Moreover, we found that prolonged CLT assessed on admission in PE patients could be helpful in identifying intermediate-risk PE patients at increased risk of death. 14 Elevated lactate has been found to contribute to both unfavorably modified fibrin clot characteristics in acute PE patients.…”

Section: Introductionmentioning

confidence: 84%

“…14 Moreover, we found that prolonged CLT assessed on admission in PE patients could be helpful in identifying intermediate-risk PE patients at increased risk of death. 14 Elevated lactate has been found to contribute to both unfavorably modified fibrin clot characteristics in acute PE patients. 15 Based on analysis of thromboemboli retrieved from patients with PE during embolectomy, more tightly packed fibrin fibers have been shown in segmental pulmonary arteries compared with those removed from lobar branches, suggesting that the fibrin architecture can reflect embolus resistance to fibrinolysis.…”

Section: Introductionmentioning

confidence: 84%

“…Definitions of right ventricular dysfunction, VTE, heart failure, and chronic obstructive pulmonary disease (COPD) were described previously. 14 The Jagiellonian University Ethical Committee approved the study, and participants provided informed written consent.…”

Section: Patientsmentioning

confidence: 99%

“…First, the number of patients was limited. However, patients were excluded from the study according to the prespecified criteria 14 and our results cannot be extrapolated to high-risk PE or individuals with concomitant cancer. Since novel therapeutic strategies for high-risk PE patients are proposed, 35 fibrin clot properties and their determinants should be evaluated in such individuals in further studies.…”

Section: Thrombosis and Haemostasismentioning

confidence: 99%

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Loose Fibrin Clot Structure and Increased Susceptibility to Lysis Characterize Patients with Central Acute Pulmonary Embolism: The Impact of Isolated Embolism

et al. 2020

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Background Prothrombotic fibrin clot properties are associated with higher early mortality risk in acute pulmonary embolism (PE) patients. It is unknown whether different types of PE are associated with particular clot characteristics. Methods We assessed 126 normotensive, noncancer acute PE patients (median age: 59 [48–70] years; 52.4% males), who were categorized into central versus peripheral PE with or without concomitant deep vein thrombosis (DVT). Plasma fibrin clot permeability (K s), clot lysis time (CLT), thrombin generation, platelet-derived markers, and fibrinolytic parameters were measured on admission. Plasma fibrin clot morphology was assessed by scanning electron microscopy (SEM). Results Patients with central PE (n = 76; 60.3%) compared with peripheral PE (n = 50; 39.7%) had 17.8% higher K s and 14.3% shortened CLT (both p < 0.01 after adjustment for potential confounders including fibrinogen), with no differences between segmental and subsegmental PE. SEM analysis demonstrated larger fibrin fiber diameter and pore size in central PE compared with peripheral PE (both p < 0.01). For isolated PE, there was 23.3% higher K s in central PE than in peripheral PE (n = 24; 19%) with no differences in other variables. Central PE combined with DVT (n = 45; 35.7%), as compared with central isolated PE (n = 31; 24.6%), was associated with shortened CLT (all p < 0.05). Conclusion Our findings suggest that looser fibrin networks composed of thicker fibers with increased susceptibility to lysis characterize patients with central PE, suggesting that fibrin clot phenotype affects the size of thrombi occluding the pulmonary arteries, highlighting the role of fibrin structures in thrombus formation and stability.

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Section: Introductionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 84%

Section: Patientsmentioning

confidence: 99%

Section: Thrombosis and Haemostasismentioning

confidence: 99%

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Loose Fibrin Clot Structure and Increased Susceptibility to Lysis Characterize Patients with Central Acute Pulmonary Embolism: The Impact of Isolated Embolism

et al. 2020

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“…Fibrin clots enriched in histone-DNA complexes had higher stability, rigidity, and prolonged clot lysis time [14]. NETs have been shown to increase in vitro thrombin generation in septic patients' blood [15]. As far as we know, there are no reports showing whether lactate concentrations in acute PE patients are linked to the prothrombotic changes in circulating blood.…”

Section: Introductionmentioning

confidence: 99%

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

Ząbczyk

Natorska

Janion−Sadowska

et al. 2020

JCM

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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.

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Reduced fibrin clot permeability on admission and elevated E-selectin at 3 months as novel risk factors of residual pulmonary vascular obstruction in patients with acute pulmonary embolism

Stępień,

Ząbczyk,

Kopytek

et al. 2023

J Thromb Thrombolysis

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Background Residual pulmonary vascular obstruction (RPVO) is common following pulmonary embolism (PE) but its association with fibrin clot properties is poorly understood. We investigated whether prothrombotic state and hypofibrinolysis markers can identify patients with RPVO. Methods In 79 normotensive noncancer patients (aged 56 ± 13.3 years) with acute PE, we determined fibrin clot permeability (Ks), clot lysis time (CLT), endogenous thrombin potential (ETP), fibrinolysis proteins, oxidative stress markers, and E-selectin on admission before initiation of anticoagulant therapy, after 5–7 days, and 3 months of anticoagulation. RPVO was diagnosed using computed tomography angiography 3–6 months since PE. Results Patients with RPVO (n = 23, 29.1%) had at baseline higher simplified Pulmonary Embolism Severity Index (sPESI) (P = 0.004), higher N-terminal brain natriuretic propeptide (P = 0.006) and higher D-dimer (P = 0.044). Patients with versus without RPVO had lower Ks (P < 0.001) and longer CLT (P < 0.05), both at baseline and 5–7 days since admission, but not at 3 months. Patients with RPVO showed 40.6% higher E-selectin (P < 0.001) solely at 3 months. By multivariable logistic regression, baseline Ks (odds ratio [OR] 0.010, 95% confidence interval [CI] 0.001–0.837, P = 0.042, per 10− 9 cm2), baseline D-dimer (OR 1.105, 95% CI 1.000-1.221, P = 0.049, per 100 ng/ml), and E-selectin levels after 3 months (OR 3.874, 95% CI 1.239–12.116, P = 0.020, per 1 ng/ml) were associated with RPVO. Conclusions RPVO patients despite anticoagulation characterize with the formation of denser fibrin clots on admission and higher E-selectin at 3 months. Those parameters could be the potential novel RPVO risk factors that warrant further evaluation in an independent cohort. Graphical Abstract

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Prothrombotic fibrin clot properties associated with NETs formation characterize acute pulmonary embolism patients with higher mortality risk

Cited by 36 publications

References 28 publications

Loose Fibrin Clot Structure and Increased Susceptibility to Lysis Characterize Patients with Central Acute Pulmonary Embolism: The Impact of Isolated Embolism

Loose Fibrin Clot Structure and Increased Susceptibility to Lysis Characterize Patients with Central Acute Pulmonary Embolism: The Impact of Isolated Embolism

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

Reduced fibrin clot permeability on admission and elevated E-selectin at 3 months as novel risk factors of residual pulmonary vascular obstruction in patients with acute pulmonary embolism

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