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Experimental and Imaging Techniques for Examining Fibrin Clot Structures in Normal and Diseased States
Published on: April 1, 2015
The Hypofibrinolysis State Associated with the Dysfibrinogenemia Dusart is Mainly Related to the Altered Fibrin Clot
Rita Marchi1, Éva Katona2, Stéphane Durual3
1Division of Angiology and Hemostasis, Department of Medicine, University Hospitals of Geneva, University of Geneva, Geneva, Switzerland.
Insights
The fibrinogen Dusart mutation creates abnormal fibrin clots highly resistant to lysis, increasing thrombosis risk. This occurs due to compact fibrin networks, not imbalances in fibrinolysis factors.
Area of Science:
- Hematology
- Molecular Biology
- Biochemistry
Background:
- Dysfibrinogenemia, like fibrinogen Dusart (p.Aα573Arg>Cys), is linked to elevated thrombosis risk.
- The underlying mechanisms causing the hypofibrinolytic state in fibrinogen Dusart remain unclear.
- Understanding these mechanisms is crucial for managing thrombotic complications.
Purpose of the Study:
- To investigate factors contributing to the hypofibrinolytic state associated with the fibrinogen Dusart mutation.
- To elucidate the role of fibrin clot structure in the thrombotic risk of this dysfibrinogenemia.
- To analyze fibrin formation, lysis, and clot architecture in detail.
Main Methods:
- Quantified fibrin α2-antiplasmin (α2-AP) incorporation using ELISA.
- Assessed fibrin formation and lysis via turbidity measurements.
- Evaluated global fibrinolytic capacity (GFC) using the Lysis timer device.
- Measured plasmin generation and clot growth dynamics (Thrombodynamics).
- Characterized fibrin clot structure using permeation studies and Scanning Electron Microscopy (SEM).
Main Results:
- Plasma levels of key fibrinolytic regulators (D-dimer, PAI-1, FXIII, PAP, α2-AP) and α2-AP incorporation were normal.
- Patient clots exhibited increased resistance to fibrinolysis (higher GFC) and transparency.
- Elevated endogenous plasmin potential and peak plasmin were observed.
- Thrombodynamics showed prolonged clot formation lag time and reduced initial growth velocity.
- SEM revealed abnormally compact fibrin networks with reduced pore size and thin fibers.
Conclusions:
- The procoagulant phenotype in fibrinogen Dusart is primarily driven by the formation of abnormally compact fibrin networks.
- This altered fibrin structure impairs perfusion and confers resistance to fibrinolysis, independent of regulatory factor imbalances.
- Fibrin clot structure plays a critical role in the thrombotic risk associated with this dysfibrinogenemia variant.
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.
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