Fibrinogen β chain and FXIII polymorphisms affect fibrin clot properties in acute pulmonary embolism

Abstract

Background Prothrombotic fibrin clot properties, including increased clot density, are in part genetically determined. We investigated whether fibrinogen alpha‐chain gene (FGA) c.991A>G (rs6050), fibrinogen beta chain gene (FGB) −455G>A (rs1800790) and factor XIII gene (F13) c.103G>T (rs5985) polymorphisms affect plasma fibrin clot properties in patients with acute pulmonary embolism (PE). Methods As many as 126 normotensive patients with PE, free of cancer, were genotyped by TaqMan assay. Fibrin clot permeability (Ks), clot lysis time (CLT) and endogenous thrombin potential (ETP) were assessed on admission. Results The minor allele frequencies were as follows: FGA rs6050 (n = 62, 0.31), FGB rs1800790 (n = 40, 0.17) and F13 rs5985 (n = 49, 0.23). There were no differences related to any of the polymorphisms with regard to demographic, clinical and laboratory data, except for fibrinogen concentration, which was higher in carriers of F13 rs5985 polymorphism (p = .024), and PE combined with deep‐vein thrombosis, which was less prevalent in FGB rs1800790 polymorphism carriers (p = .004). Carriers of FGB rs1800790 A allele and F13 rs5985 T allele had lower Ks, prolonged CLT and higher ETP compared with major homozygotes (all p < .05). After adjustment for fibrinogen, all differences remained significant (all p < .01). There were no associations between the FGA rs6050 polymorphism and Ks, CLT or ETP. Conclusion Our study showed that FGB rs1800790 and F13 rs5985 polymorphisms contribute to the prothrombotic fibrin clot phenotype and these effects are strong enough to be observed in the acute phase of PE.

Fibrinogen and Factor XIII in Venous Thrombosis and Thrombus Stability

“…Failure of timely dissolution of PE can result in chronic thromboembolic pulmonary hypertension, right heart failure, and cardiogenic shock. 118 Clinical observations [119][120][121][122][123] and experimental studies with mice [124][125][126] support roles for both fibrin(ogen) and FXIII(a) in maintaining venous thrombus stability and preventing embolization.…”

“…120,121,[128][129][130][131] The fibrinogen β chain (FGB [rs1800790]) and FXIII Val34Leu polymorphisms have been implicated as determinants of altered clot properties in acute PE. 123 Using intravital video microscopy and lung histology of a FeCl 3 -induced model of acute thrombosis, Gross and co-workers found reduced thrombus stability and increased emboli in mice treated with the direct thrombin inhibitor dabigatran and in FXIII-deficient mice, leading to the hypothesis that by reducing thrombin production, anticoagulant treatment reduces activation of FXIII and the thrombin-activatable fibrinolysis inhibitor and decreases thrombus stability. 132 They subsequently showed that supplementation with FXIII stabilizes venous thrombi and decreases embolization without altering thrombus size.…”

“…120,121,128–131 The fibrinogen β chain ( FGB [rs1800790]) and FXIII Val34Leu polymorphisms have been implicated as determinants of altered clot properties in acute PE. 123…”

Causal association between circulating blood cell traits and pulmonary embolism: a mendelian randomization study

“…PE is often categorized together with deep vein thrombosis (DVT) as venous thromboembolism (VTE), and they both share common risk factors, including venous stasis, hypercoagulability, and endothelial damage. Two large-scale genome-wide association studies (GWASs) have identified 34 and 22 independent genetic signals associated with VTE risk [ 7 , 8 ], primarily involving loci related to coagulation and fibrinolytic, respectively [ 9 , 10 ]. In addition, circulating cytokines, blood pressure and blood metabolites have been linked to an increased risk of VTE [ 11 – 13 ].…”

Genetic Markers for Thrombophilia and Cardiovascular Disease Associated with Multiple Sclerosis

“…Mutations in the fibrinogen gene, particularly the transition from guanine to adenine at nucleotide 455 of the beta-fibrinogen promoter, lead to elevated fibrinogen levels. Furthermore, the −455 G>A variant has been identified as a risk factor for fibrin clot formation in PE cases [ 10 ] and predisposes to coronary artery disease, as well as cerebral infarction [ 11 , 12 ]. So far, in MS animal models, thrombin and fibrin(ogen) have been detected in pre-demyelinated CNS areas, attracting resident and infiltrating immune cells from the periphery, contributing further in abnormal BBB permeability, and stimulating the inflammatory process [ 13 ].…”