Factor XIII and Fibrin Clot Properties in Acute Venous Thromboembolism.

Michał Ząbczyk,Joanna Natorska,Anetta Undas

doi:10.3390/ijms22041607

Abstract

Coagulation factor XIII (FXIII) is converted by thrombin into its active form, FXIIIa, which crosslinks fibrin fibers, rendering clots more stable and resistant to degradation. FXIII affects fibrin clot structure and function leading to a more prothrombotic phenotype with denser networks, characterizing patients at risk of venous thromboembolism (VTE). Mechanisms regulating FXIII activation and its impact on fibrin structure in patients with acute VTE encompassing pulmonary embolism (PE) or deep vein thrombosis (DVT) are poorly elucidated. Reduced circulating FXIII levels in acute PE were reported over 20 years ago. Similar observations indicating decreased FXIII plasma activity and antigen levels have been made in acute PE and DVT with their subsequent increase after several weeks since the index event. Plasma fibrin clot proteome analysis confirms that clot-bound FXIII amounts associated with plasma FXIII activity are decreased in acute VTE. Reduced FXIII activity has been associated with impaired clot permeability and hypofibrinolysis in acute PE. The current review presents available studies on the role of FXIII in the modulation of fibrin clot properties during acute PE or DVT and following these events. Better understanding of FXIII’s involvement in the pathophysiology of acute VTE might help to improve current therapeutic strategies in patients with acute VTE.

Highlights

Factor (F) XIII, a fibrin stabilizing factor, is a 325 kDa protransglutaminase representing the transglutaminase-like superfamily, which involves calcium-dependent enzymes leading to post-translational modifications of proteins and generation of isopeptide bonds resistant to proteolytic degradation [1]
The current review presents available studies on the role of factor XIII (FXIII) in the modulation of fibrin clot properties during acute pulmonary embolism (PE) or deep vein thrombosis (DVT) and following these events
FXIII levels influence fibrin following clot composition and properture with higher that susceptibility toand lysisactivity compared to patients

Summary

Introduction

Factor (F) XIII, a fibrin stabilizing factor, is a 325 kDa protransglutaminase representing the transglutaminase-like superfamily, which involves calcium-dependent enzymes leading to post-translational modifications of proteins and generation of isopeptide bonds resistant to proteolytic degradation [1]. FXIII is present in cells, including monocytes, osteoblasts, and megakaryocytes, and in plasma [2] Both forms of FXIII are involved in blood coagulation [2]. In the presence of fibrin, thrombin converts FXIII to its activated form (FXIIIa) by cleavage of FXIII-A at Arg37-Gly and release of an activation peptide, followed by Ca2+ driven dissociation of FXIII-A and B subunits [3]. FXIII plays a critical role in crosslinking of extracellular matrix proteins, such as fibronectin, collagen or von Willebrand factor [18], which leads to FXIII-A deposition, influences cell-matrix interactions, and alters the properties of fibrin clots [22]. The impact of functional and mechanical properties of crosslinked fibrin on thrombus remodeling and its interaction with cells in vivo require further studies including use of three-dimensional in vitro models of fibrin clots. Since in vivo specific FXIIIa inhibitors are unknown, mechanisms such as proteolytic cleavage by thrombin [27] or by proteolytic enzymes of polymorphonuclear cells have been proposed to inactivate FXIIIa [28]

Genetic Variants of FXIII

FXIII as a Modulator of Fibrin Clot Properties

FXIII in Patients with Acute VTE

Factor

Findings

Drug Induced Effects on FXIII and Fibrin Properties