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

Abstract

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

TGFβ1 plasma levels and clot lysis assay to better characterize patients after a first unprovoked episode of pulmonary embolism

“…However, CLT measured three months after the thrombotic event was similar between RPVO and non-RPVO patients [22]. Taken together, these results support the absence of association between RPVO and CLT measured more than three months after PE, in line with the findings of our study.…”

“…A shorter lagphase was observed in patients with RPVO compared to patients without [21]. Endogenous thrombin potential was equivalent regardless of RPVO status [22]. While we used a different technique to evaluate clot formation, we found similar clot formation parameters measured with CLA, in particular similar lagphase and peak amplitude, in the RPVO and non-RPVO groups.…”

“…In addition, in our study, uPA plasma levels were similar between patients with or without RPVO. The association between uPA plasma levels and the presence of RPVO was not investigated in previous studies focusing on RPVO [16,21,22,33]. TFPI plasma levels were previously described as significantly increased in patients with RPVO [16].…”

“…Regarding clot formation parameters, the association between RVPO and prothrombotic phenotype was previously investigated using turbidimetric clotting assay [21] or calibrated automated thrombography [22]. A shorter lagphase was observed in patients with RPVO compared to patients without [21].…”

“…Elevated plasma factor VIII, a procoagulant factor, is associated with recurrent VTE [14] and RPVO after PE [15,16]. Decreased plasma fibrinolytic potential, as assessed by prolonged clot lysis time (CLT) measured during clot lysis assay (CLA) [17], is variably associated with recurrent VTE [18][19][20] and RPVO [21,22] after a first VTE event. In addition, venous thrombus resolution involves a complex interplay between endothelial cells, immune cells and platelets [23].…”