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Reda, S.

Publications and source records attributed to Reda, S..

2 recordsLinked to original sources
bioRxiv2023

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

pathology↗
bioRxiv2023

The Endothelium Modulates the Prothrombotic Phenotype of Factor V Leiden: Evidence from an Ex Vivo Model

BackgroundClinical expressivity of the thrombophilic factor V Leiden (FVL) mutation is highly variable. Increased activated protein C (APC) formation in response to thrombin formation has been observed in asymptomatic FVL carriers in vivo. Here we further explored this association using a recently developed endothelial colony forming cell (ECFC)-based ex-vivo model. MethodsECFCs and citrated plasma were obtained from FVL carriers with/without previous venous thromboembolism (VTE+/-, n=7 each) and seven healthy controls. Coagulation was activated by tissue factor in defibrinated recalcified plasma added to confluent cell cultures. Thrombin and APC concentration were measured over time and the respective areas under the curve (AUC) calculated. Additionally, inhibition kinetics of exogenously added APC and APC sensitivity of the prothrombinase complex were measured in plasma. Expression of thrombomodulin and endothelial protein C receptor (EPCR) on ECFCs was assessed using cell-based enzyme-linked immunosorbent assays. ResultsIn autologous plasma on ECFCs, the APC response to thrombin formation (AUC APC/AUC thrombin), was higher in FVL VTE-than FVL VTE+ patients (0.138 versus 0.028, P=0.026). APC inactivation kinetics, APC sensitivity, and thrombomodulin/EPCR expression on ECFCs did not differ between these cohorts and compared to healthy controls. Cross-over experiments with plasma from FVL VTE- and FVL VTE+ patients on non-FVL ECFCs yielded indistinguishable results. In contrast, in normal plasma on FVL VTE-ECFCs the APC response remained significantly higher than on FVL VTE+ ECFCs (0.052 versus 0.022, P=0.011). ConclusionsConsistent with results from previous in vivo experiments, APC response rates to thrombin formation were higher in asymptomatic FVL carriers compared to those with previous VTE. Our observations suggest that this increased APC response is driven by the endothelium. Further studies are warranted to elucidate yet unknown endothelial mechanisms that might modulate the clinical expressivity of FVL.

pathology↗