Fibrinolysis biomarker, thrombin, and activated protein C level alterations after coagulation activation depend on type of thrombophilia and clinical phenotype.

BACKGROUND: Recently, we have shown alterations in the anticoagulant response to recombinant activated factor VII (rFVIIa)-induced coagulation activation in patients with thrombophilia.

OBJECTIVES: This study aimed to extend this in vivo model to fibrinolysis biomarkers.

METHODS: This interventional in vivo study included 56 patients with thrombophilia and previous venous thromboembolism (VTE+), 38 without VTE (VTE-), and 35 healthy controls. Plasma levels of D-dimer, plasmin-α2-antiplasmin (PAP) complex, and plasminogen activator inhibitor-1 (PAI-1) were monitored for over 8 hours after rFVIIa infusion (15 μg/kg) along with thrombin markers and activated protein C (APC).

RESULTS: Throughout cohorts, median PAP increased by 40% to 52% ( P  < 3.9 × 10-10 ) and PAI-1 decreased by 59% to 79% ( P  < 3.5 × 10-8 ). In contrast to thrombin-antithrombin (TAT) complex, which also increased temporarily (44% to 115%, P  < 3.6 × 10-6 ), changes in PAP and PAI-1 did not reverse during the observation period. The area under the measurement-time curves (AUCs) of PAP and TAT, which are measures of plasmin and thrombin formation, respectively, were each greater in the VTE+ cohort than in healthy controls (median PAP-AUC = 0.48 vs 0.27 ng·h/L [ P  = .003], TAT-AUC = 0.12 vs 0.03 nmol·h/L [ P  = 2.5 × 10-4 ]) and were correlated with one another ( r  = 0.554). As evidenced by the respective AUCs, asymptomatic factor (F)V Leiden carriers showed less PAP formation (0.22 vs 0.41 ng·h/L, P  = 9 × 10-4 ), more pronounced PAI-1 decline (0.10 vs 0.18 ng·h/L, P  = .01), and increased APC formation (28.7 vs 15.4 pmol·h/L, P  = .02) than those within the VTE+ group ( n  = 19 each).

CONCLUSION: rFVIIa-induced thrombin formation is associated with fibrinolysis parameter changes outlasting the concomitant anticoagulant response. Both correlate with thrombosis history in FV Leiden and might help explain its variable clinical expressivity.