Factor XIII deficiency does not prevent FeCl3‐induced carotid artery thrombus formation in mice

Abstract

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made. AbstractBackground: The compositions of venous (red blood cell-rich) and arterial (plateletrich) thrombi are mediated by distinct pathophysiologic processes; however, fibrin is a major structural component of both. The transglutaminase factor XIII (FXIII) stabilizes fibrin against mechanical and biochemical disruption and promotes red blood cell retention in contracted venous thrombi. Previous studies have shown factor XIII (FXIII) inhibition decreases whole blood clot mass and therefore, may be a therapeutic target for reducing venous thrombosis. The role of FXIII in arterial thrombogenesis is less studied, and the particular contribution of platelet FXIII remains unresolved.Objective: To determine whether FXIII reduction prevents experimental arterial thrombogenesis.Methods: Using wild-type mice and mice with genetically imposed deficiency in FXIII, we measured thrombus formation and stability following ferric chloride-induced arterial thrombosis. We also determined the impact of FXIII on the mass of contracted platelet-rich plasma clots.Results: Following vessel injury, F13a +/+ , F13a +/− , and F13a −/− mice developed occlusive arterial thrombi. FXIII deficiency did not significantly reduce the incidence or prolong the time to occlusion. FXIII deficiency also did not alter the timing of reflow events or decrease platelet-rich clot mass.Conclusions: FXIII does not significantly alter the underlying pathophysiology of experimental arterial thrombus formation. K E Y W O R D Sfactor XIII, ferric chloride, fibrinogen, platelets, thrombosis, transglutaminase Essentials • Factor XIII (FXIII) stabilizes fibrin and promotes red cell retention in venous thrombi.• The role of FXIII in arterial thrombosis is less understood.• FXIII deficiency does not prevent ferric chloride-induced carotid artery thrombus formation in mice.• FXIII has nonoverlapping roles in venous and arterial thrombosis.

Novel venous thromboembolism mouse model to evaluate the role of complete and partial factor XIII deficiency in pulmonary embolism risk

“…For example, compared to FXIII‐sufficient mice ( F13 +/+ ), FXIII‐deficient mice ( F13a −/− ) show increased bleeding following tail transection, but not saphenous vein puncture 42 50,51 but reduced stasis‐ or stenosis‐induced VT 8,42 . Collectively, these and other studies of FXIII function ( 8,11–13,42,50,52–54 and present work) suggest FXIII has non‐overlapping roles in venous and arterial thrombosis.…”

“…For example, compared to FXIIIsufficient mice (F13 +/+ ), FXIII-deficient mice (F13a −/− ) show increased bleeding following tail transection, but not saphenous vein puncture. 42 Moreover, mice with reduced FXIII antigen (F13a +/− or F13a −/− ) or delayed FXIII activation (Fibγ 390−396A ) have normal arterial thrombus formation and no measurable reflow events following FeCl 3 injury, 50,51 but reduced stasis-or stenosisinduced VT. 8,42 Collectively, these and other studies of FXIII function ( 8,(11)(12)(13)42,50,(52)(53)(54) and present work) suggest FXIII has nonoverlapping roles in venous and arterial thrombosis. Thus, a major aspect of the current work investigating VTE is the use of a mouse model that recapitulates key aspects of VTE in humans.…”

The factor XIII‐A Val34Leu polymorphism decreases whole blood clot mass at high fibrinogen concentrations

“…In contrast, our in vitro clot contraction model recapitulates aspects of venous thrombosis in which stasis induces formation of RBC‐rich thrombi that undergo subsequent clot contraction and consolidation. Indeed, we have observed differences in the contribution of FXIII to thrombi triggered by FeCl 3 under flow and thrombi triggered by venous stasis, suggesting different effects of the FXIII V34L polymorphism on clot size in these two studies stem from differences in the role of FXIII in these experimental models.…”

“…20 In contrast, our in vitro clot contraction model recapitulates aspects of venous thrombosis in which stasis induces formation of RBC-rich thrombi that undergo subsequent clot contraction and consolidation. Indeed, we have observed differences in the contribution of FXIII to thrombi triggered by FeCl 3 under flow 33 and thrombi triggered by venous stasis, 24,25 suggesting F I G U R E 1 In reconstituted whole blood with human donor plasma, the FXIII 34Leu variant mitigates the effect of high fibrinogen concentration on contracted clot mass. A, Platelet-poor plasmas from 86 healthy donors (40 FXIII Val/Val , 28 FXIII Val/Leu , and 18 FXIII Leu/ Leu ) were reconstituted with washed platelets and O-negative red blood cells.…”

Role of Neutrophils and NETs in Animal Models of Thrombosis

“…These models consist of the use of animals genetically modified for the proteins involved in coagulation. In particular, we found in the literature mouse lines with modifications of the sequences coding for tissue factor pathway inhibitor (TFPI), antithrombin (AT), protein C (PC), and its entire signaling pathway, including thrombomodulin (TM), endothelial protein C receptor (EPCR), Factor XIII [51] and Factor V (or Factor V Leiden, FVL) [52].…”