The Hypofibrinolysis State Associated with the Dysfibrinogenemia Dusart is Mainly Related to the Altered Fibrin Clot Structure.

Abstract

The fibrinogen Dusart (p.Aα573Arg > Cys) is a dysfibrinogenemia associated with an increased risk of thrombosis. The aim of this study was to identify factors that could explain the hypofibrinolytic state associated with the Dusart mutation.The fibrin α2-antiplasmin (α2-AP) incorporation was quantified by a homemade enzyme-linked immunosorbent assay. The fibrin formation and lysis were studied by turbidity at 405 nm, and the global fibrinolytic capacity (GFC) with the Lysis timer device. The plasmin generation was assessed through an automated method. The clot growth was examined using Thrombodynamics. The clot structure was evaluated by measuring the permeation constant and scanning electron microscopy (SEM).The plasma levels of D-dimer, PAI-1, FXIII, PAP, and α2-AP were within the normal range, as was α2-AP incorporation into fibrin. By turbidity the patient's clots were almost transparent, and very resistant to fibrinolysis. The patient's GFC was 51 minutes compared with 45 minutes in control. The patient's endogenous plasmin potential and the peak plasmin were increased. The Thrombodynamics analysis revealed an increased lag time and a decreased initial velocity of patient's clot growth. The fibrin clot structure was characterized by a strong reduction in clot's flow (small pores size), and very thin fibers.The patient's procoagulant phenotype appears primarily driven by the formation of abnormally compact fibrin networks, leading to impaired perfusion and resistance to fibrinolysis, independent of any imbalance in fibrinolytic activators or inhibitors. These findings highlight the critical role of the fibrin clot structure in the thrombotic risk of this variant.