What is the role of factor XIII (FXIII) cross-linking and resistance to lysis in the pathophysiology of factor XIII (FXIII) deficiency?

Updated: Aug 01, 2019
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Perumal Thiagarajan, MD  more...
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FXIIIa cross-links the lysine of one g chain in the fibrin polymer with the glutamine of another g chain by transamidation, releasing ammonia in the process. Additional cross-links occur between a-a chains, a-g chains, a chains-a2 -plasmin inhibitor (a2 PI), and a chains-fibronectin. As a result of the extensive cross-linking actions of FXIIIa, the clot structure of fibrin polymers increases in complexity from dimers to trimers to tetramers.

The g chains of fibrinogen and fibrin normally bind to the platelet membrane glycoprotein IIb/IIIa complex. The same g chains are subject to cross-linking by FXIIIa; therefore, cross-linking also occurs between fibrin and the platelet membrane. Both plasma FXIIIa and platelet FXIIIa cross-link fibrin polymers, but under physiologic conditions, platelet FXIII is believed to play a minor role. [34] Red cell FXIII is responsible for hybrid cross-linking of a-g chains, in contrast to the actions of plasma FXIII.

Dysfibrinogenemias and dyshypofibrinogenemias result in alterations in fibrin (substrate for FXIIIa), which can interfere with the ability of FXIII to cross-link fibrin. A reduction in available fibrin resulting from afibrinogenemia can have the same effect. Conversely, increased fibrinogen levels have been identified as a risk factor for thrombosis.

Mechanisms of this risk were elucidated by a fibrinolysis assay containing purified components. The assay showed that lysis of fibrin decreased as fibrinogen levels increased, and the presence of a minor common variant of fibrin (g') is associated with accelerated cross-linking, which made the clot resistant to proteolysis by both plasmin and trypsin. Increased clot stability also was believed to result from increased concentration of FXIII in the clot. Non-cross-linked fibrin potentiates activation of FXIII by thrombin; thus, the substrate potentiates its enzyme, further contributing to clot stability. [25, 35, 36]

Cross-linking of a2 PI to a chains of fibrin by FXIIIa brings the principal inhibitor of plasmin to the site of the clot, ensuring resistance of the clot to proteolysis. Inhibition of a2 PI in in vitro systems leads to enhanced clot lysis. In humans, deficiency of a2 PI results in a bleeding disorder because of vulnerability of the fibrin clot to prompt degradation by plasmin. The formation of highly cross-linked a-fibrin polymers in the presence of high concentrations of FXIIIa produces clots that are highly resistant to fibrinolysis. [37]

Fibronectin, an adhesive protein, is a large component (approximately 4%) of the proteins in a fibrin clot, is present in plasma and cells, and is subject to cross-linking by both plasma and cellular FXIII. Cross-linking of fibronectin to fibronectin and fibronectin to fibrin is accomplished by FXIIIa, with fibronectin contributing to increased fiber size, density, and strength of the clot. FXIIIa also cross-links actin to fibrin and actin to myosin. Cross-linking of intracellular structural proteins is involved in clot retraction and cell migration. This complex gel network created by the actions of FXIII plays an important role in wound healing, cell adhesion, and cell migration. All of these cross-linking reactions impart increased mechanical strength to the clot, contributing to clot retraction and resistance of the clot to degradation by plasmin and providing an explanation for the known plasmin resistance of older clots.

Many other proteins function as substrates for FXIIIa, including von Willebrand factor (vWF), factor V (FV), thrombospondin, gelsolin, vitronectin, vinculin, lipoprotein (a), and collagen (FXIIIa cross-links collagen with fibronectin and vWF, attaches the clot to the vessel wall, impacts tissue repair, increases resistance of collagen to proteolysis, and modulates synthesis of collagen by fibroblasts). Thus, FXIII plays a role in a wide array of cross-linking reactions involving plasma proteins at the intracellular level, impacting many different functions.

Note that because of the lack of cross-linking in individuals with FXIII deficiency, their D-dimer level will remain low, even if they experience thrombosis, although levels of other fibrin degradation products will be increased. Consequently, the D-dimer assay is not reliable for screening in these patients.

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