Fibrinolytic Status and Risk of Death After Acute Pulmonary Embolism

Abstract

Background Acute pulmonary embolism (PE) is a heterogeneous disease process with variable presentation and outcomes. The endogenous fibrinolytic system is a complex framework of regulatory pathways that maintains homeostasis by dissolving overabundant thrombi. We sought to investigate phenotypic profiles of the endogenous fibrinolytic system among patients presenting with acute PE and their impact on mortality. Methods We enrolled all consecutive patients with acute PE in our institutional Pulmonary Embolism Response Team registry. We collected blood samples at the time of PE diagnosis and analyzed concentrations of plasminogen activator inhibitor 1 (PAI-1), thrombin-activatable fibrinolysis inhibitor (TAFI), and alpha-2-antiplasmin (A2A). We assessed the association of concentration of fibrinolytic inhibitors and 1-year all-cause mortality and various echocardiographic markers of right ventricular (RV) dysfunction. Results There is significant variability of PAI-1, A2A, and TAFI concentrations across the spectrum of PE risk profiles with high PAI-1, low TAFI, and low A2A (herein referred to as a high-risk biomarker profile) correlating with worse PE severity. High-risk biomarker profile correlated with high-risk echocardiographic features of RV dysfunction, including increased RV/left ventricular (LV) ratio, low tricuspid annular plane systolic excursion, and low right ventricular outflow tract velocity time integral. Higher-risk biomarker profile was able to discriminate and independently identify patients at high risk of all-cause mortality (Group 2 HR 6 95% CI 1.3-27.8, Group 3 HR 12, 95% CI 1.7-86). Conclusions Further studies are needed to assess the exact pathophysiological link between fibrinolytic status and poor outcome after acute PE and to ascertain the impact of anti-inhibitors of the fibrinolytic system on response to therapy and outcomes after acute PE.

The Fibrinolytic System and Its Measurement: History, Current Uses and Future Directions for Diagnosis and Treatment

“…However, intermediate-to-high-risk PE patients have significantly longer lysis time than low-and-intermediate-risk PE patients [ 69 ]. High PAI-1, low TAFI, and low α2-antiplasmin indicate a high-risk biomarker profile in acute PE [ 105 ]. This may be of clinical importance when evaluating the results of catheter-based therapy and thrombolysis in PE.…”

Decreased Thrombin Generation is Associated with Increased Thrombin Generation Biomarkers and Blood Cellular Indices in Pulmonary Embolism

“…The pathogenesis of thromboembolism in PE is complex, involving various mechanisms including inflammation, hemostatic dysregulation, fibrinolytic deficit, cellular, and vascular dysfunctions. 3 – 5 Additionally, risk factors such as obesity, contraceptive use, pregnancy, immobilization, chemotherapy, and anticoagulation also contribute to VTE development. 6 – 15 Furthermore, genetic predispositions like FV-Leiden, prothrombin gene mutation (G20210), and deficiencies in anti-thrombin III, protein C, and protein S), alongside hyperhomocysteinemia and MTHFR mutation, play significant roles in VTE pathophysiology.…”

Identification of Genes and miRNAs Associated with TAFI-Related Thrombosis: An in Silico Study

“…Following thrombin activation, TAFI downregulates fibrinolysis, thus linking the latter with coagulation [ 5 ]. Two pools of TAFI are present in blood, the plasma pool and the platelet pool, which is only secreted upon platelet activation and accounts for less than 0.1% of total blood TAFI [ 7 , 8 ].…”

“…The AtheroGene study also found that the amount of TAFIa is independently associated with the risk of death from cardiovascular causes [ 9 ]. Notably, in the context of acute pulmonary embolism (PE), low TAFI concentrations and low alpha-2-antiplasmin correlated with worse PE severity [ 7 ]. Yet, other studies have reported opposing findings as to TAFI levels in the aforementioned disease categories.…”