Coagulation activation-induced fibrinolysis biomarker changes depend on thrombophilic risk factors and their clinical phenotype: an interventional in vivo study

BackgroundRecently we have shown alterations in the anticoagulant response to recombinant activated factor VII (rFVIIa)-induced coagulation activation in patients with thrombophilia. ObjectivesHere we extended this in vivo model to study fibrinolysis biomarkers. MethodsThe 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-2-antiplasmin complex (PAP), and plasminogen activator inhibitor-1 (PAI-1) were monitored over 8 hours after rFVIIa infusion (15 {micro}g/kg) along with thrombin activation markers and activated protein C (APC). ResultsIn all cohorts, PAP increased (P<3.9{middle dot}10-10) and PAI-1 decreased (P<3.5{middle dot}10-8). In contrast to thrombin-antithrombin complex (TAT), which also increased temporarily in all cohorts (P<3.6{middle dot}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{middle dot}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{middle dot}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. ConclusionrFVIIa-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. EssentialsO_LIImpairment of fibrinolysis might result in increased risk of thrombosis. C_LIO_LIWe studied fibrinolytic biomarkers after coagulation activation by recombinant factor VIIa. C_LIO_LIHereby induced alterations in fibrinolytic biomarkers outlast concomitant anticoagulant changes. C_LIO_LIFactor V Leiden carriers with or without thrombosis showed distinct fibrinolytic changes. C_LI