Coagulation activation-induced fibrinolysis biomarker changes depend on thrombophilic risk factors and their clinical phenotype: an interventionalin vivostudy

Background Recently we have shown alterations in the anticoagulant response to recombinant activated factor VII (rFVIIa)-induced coagulation activation in patients with thrombophilia. Objectives Here we extended this in vivo model to study fibrinolysis biomarkers. Methods The study population included 56 patients with thrombophilia and a history of venous thromboembolism (VTE+), 38 asymptomatic patients with thrombophilia (VTE-) and 35 healthy controls. Plasma levels of D-dimer, plasmin-α2-antiplasmin complex (PAP), and plasminogen activator inhibitor-1 (PAI-1) were monitored over 8 hours after rFVIIa infusion (15 µg/kg) along with thrombin activation markers and activated protein C (APC). Results In all cohorts, PAP increased ( P <3.9·10 -10 ) and PAI-1 decreased ( P <3.5·10 -8 ). In contrast to thrombin-antithrombin complex (TAT), which also increased temporarily in all cohorts ( P <3.6·10 -6 ), changes of PAP and PAI-1 did not reverse during the observation period. The area under the curve (AUC) of PAP (respectively TAT), as measure of plasmin (respectively thrombin) formation, was greater in the VTE+ cohort than in healthy controls (PAP AUC P =0.003, TAT AUC P =2.5·10 -4 ) and showed correlation (r=0.554). As evidenced by the respective AUCs, asymptomatic factor V Leiden (FVL) carriers in the VTE-cohort showed less PAP formation ( P =9·10 -4 ), more pronounced PAI-1 decline ( P =0.010), and increased APC formation ( P =0.020) than those within the VTE+ group (n=19 each). This was not observed in prothrombin 20210G>A carriers or patients with unexplained familial thrombophilia. Conclusion rFVIIa-induced thrombin formation is associated with fibrinolysis parameter changes outlasting the concomitant anticoagulant response. Both correlate with thrombosis history in FVL and might help to explain its variable clinical expressivity. Essentials Impairment of fibrinolysis might result in increased risk of thrombosis. We studied fibrinolytic biomarkers after coagulation activation by recombinant factor VIIa. Hereby induced alterations in fibrinolytic biomarkers outlast concomitant anticoagulant changes. Factor V Leiden carriers with or without thrombosis showed distinct fibrinolytic changes.