Association of NT-proBNP and GDF-15 with markers of a prothrombotic state in patients with atrial fibrillation off anticoagulation

Abstract

We investigated whether growth differentiation factor-15 (GDF-15), also known as macrophage inhibitory cytokine-1 (MIC-1), levels are associated with a prothrombotic state in atrial fibrillation (AF) as compared to N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I (cTnI-hs). In 103 patients with AF assessed off anticoagulation (age: 71.0 [65.0-76.0] years; CHA 2 DS 2 -VASc score: 4.6 ± 1.7), we measured endogenous thrombin potential (ETP), plasma fibrin clot permeability (K s , a measure of clot density) and clot lysis time (CLT) and other hemostatic parameters, along with GDF-15, NT-proBNP, and cTnI-hs. GDF-15 positively correlated with ETP and CLT (r = 0.25, P = 0.01 and R = 0.56, P < 0.0001, respectively) but not with K s , von Willebrand factor, thrombin-activatable fibrinolysis inhibitor, plasminogen, antiplasmin or tissue-type plasminogen activator antigen. NT-proBNP showed a stronger association with ETP (r = 0.60, P < 0.0001) and a similar correlation with CLT (R = 0.53, P < 0.0001), while cTnI-hs correlated solely with CLT (R = 0.25, P = 0.01). After adjustment for clinical and laboratory parameters, GDF-15 was a better independent predictor of CLT (unstandardized coefficient B 0.009; 95% confidence interval [CI] 0.006-0.012) than NT-proBNP (B 0.007; 95% CI 0.004-0.010, R (2) = 0.51; P < 0.0001); while among the three biomarkers, only NT-proBNP was an independent predictor of ETP. Elevated GDF-15 and NT-proBNP independently predict impaired fibrin clot lysability, while NT-proBNP is a key predictor of heightened thrombin formation in AF. Our findings suggest that a predictive value of NT-proBNP and GDF-15 in AF could be in part attributed to their association with prothrombotic blood alterations.

Chronic Kidney Disease and Its Impact on a Prothrombotic State in Patients with Atrial Fibrillation

“…We collected demographic and clinical data. Types of AF and risk factors were defined according to the European Society of Cardiology guidelines [10]. Stage 3 and 4 CKD were defined as eGFR 30-59 mL/min/1.73 m 2 and 15-29 mL/min/1.73 m 2 , respectively.…”

“…Patients with AF have been reported to show increased fibrin clot density and decreased clot lysability [8]. These unfavorable fibrin clot properties, the so-called prothrombotic clot phenotype, have been found to be associated with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and growth differentiation factor-15 [9,10]. Recently, it has been demonstrated that low plasma clot permeability and prolonged clot lysis can predict ischemic stroke or transient ischemic attack in AF during follow-up [11,12].…”

“…Thrombotic and hemostatic alterations in patients with CKD at least in part result from the uremic milieu associated with accumulation of uremic toxins [18]. However, most AF studies focused on prothrombotic abnormalities excluded patients with stage 4 CKD or their number was small [9][10][11][12]16].…”

The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study

“…As AF is one of the most common risk factors for CES, some studies showed that GDF-15 could promote thrombosis in patient with AF by inhibiting anticoagulation. AF patients with high serum GDF-15 levels (range from 1661.0 to 5163.0 pg/mL) had 19.2% longer clot lysis time (CLT) (range from 94.3 to 117.5 min), indicating that elevation of serum GDF-15 levels drives anti-fibrinolytic reactions unrelated to increased plasminogen activator inhibitor-1 (PAI-1) or antiplasmin [ 29 ]. Taken together, circulating GDF-15 levels might exert a predictive value of CES in AF patients attributed to its prothrombotic effects.…”

The impact of growth differentiation factor 15 on the risk of cardiovascular diseases: two-sample Mendelian randomization study

“…As AF is one of the most common risk factors for CES, some studies showed that GDF-15 could promote thrombosis in patient with AF by inhibiting anticoagulation. AF patients with high serum GDF-15 levels (range from 1661.0 to 5163.0 pg/mL) had 19.2% longer clot lysis time (CLT) (range from 94.3 to 117.5 min), indicating that elevation of serum GDF-15 levels drives anti-brinolytic reactions unrelated to increased plasminogen activator inhibitor-1 (PAI-1) or antiplasmin [29]. Taken together, circulating GDF-15 levels might exert a predictive value of CES in AF patients attributed to its prothrombotic effects.…”