Lytic Susceptibility, Structure, and Mechanical Properties of Fibrin in Systemic Lupus Erythematosus.

Rustem I Litvinov,Rosa M Nabiullina,Laily D Zubairova,John W Weisel,Izabella A Andrianova,Mileusha A Shakurova

doi:10.3389/fimmu.2019.01626

Abstract

Among complications of systemic lupus erythematosus (SLE), thrombotic events are relatively common and contribute significantly to the morbidity and mortality rates. An increased risk of thrombosis in various diseases has been shown to be associated with the lytic stability and mechanical stiffness of the fibrin clot determined by its structure. Here we studied alterations of the fibrin clot properties in relation to disease severity in SLE patients. Plasma clots from 28 SLE patients were characterized by the kinetics of formation and fibrinolytic dissolution (using dynamic turbidimetry), the network and fiber ultrastructure (scanning electron microscopy), viscoelasticity (shear rheometry), and the rate and degree of crosslinking (Western blotting) correlated with the disease activity, blood composition, and compared to clotting of pooled normal human plasma. Clots made from plasma of SLE patients were lysed faster with exogenous t-PA than control clots from normal plasma without a significant difference between those from active (SLEDAI>4) and inactive (SLEDAI<4) SLE patients. Clots from the blood of patients with active SLE were characterized by significantly slower onset, but faster rate of fibrin polymerization and a higher optical density due to thicker fibers compared to those from inactive SLE and control pooled normal plasma. The rheological parameters of the clots (storage and loss moduli) were significantly increased in the active SLE patients along with enhanced fibrin crosslinking and hyperfibrinogenemia. The structural and rheological alterations displayed a strong positive correlation with high fibrinogen levels and other laboratory markers of immune inflammation. In conclusion, changes in the blood composition associated with active systemic inflammation in SLE cause significant alterations in the lytic resistance of fibrin clots associated with changes in polymerization kinetics, viscoelastic properties, and structure. The formation of more rigid prothrombotic fibrin clots in the plasma of SLE patients is likely due to the inflammatory hyperfibrinogenemia and greater extent of crosslinking. However, the higher susceptibility of the SLE clots to fibrinolysis may be a protective and/or compensatory mechanism that reduces the risk of thrombotic complications and improves patient outcomes.

Highlights

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with possible involvement of various organs and systems as well as varying manifestations and severity of the clinical course and outcomes
These results indicate that fibrin clots from SLE patients are more susceptible to the t-PA-induced internal fibrinolysis than clots from healthy subjects and that this higher proteolytic susceptibility is maintained irrespective of the degree of disease activity
To establish the relationship between the lytic susceptibility and quantitative and/or qualitative changes in fibrin clots made from the blood of SLE patients, we analyzed the kinetics of fibrin formation, clot structure, the extent of crosslinking, and mechanical properties with respect to variations in fibrinogen concentrations and other clinical and laboratory features of SLE

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with possible involvement of various organs and systems as well as varying manifestations and severity of the clinical course and outcomes. Thrombotic events are quite common in SLE, with the incidence that is 25- to 50-fold higher than in the general population [5] indicating that SLE itself is an independent risk factor for developing both arterial and venous thrombosis. The incidence of thrombosis depends on the clinical and laboratory characteristics of SLE and could further increase when SLE is associated with other general, demographic risk factors or with inherited or acquired pro-thrombotic abnormalities [6,7,8]. Thrombosis appears to be one of the most common causes of death in SLE; thrombotic events and cardiovascular accidents can be the first complications of SLE after reactivation of the disease [3, 9]

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Conclusion