Transglutaminase (Factor XIII) in Coagulation
Primary Role and Mechanism
Factor XIII is a thrombin-activated transglutaminase that stabilizes fibrin clots by cross-linking fibrin chains, making them mechanically stronger and more resistant to degradation by plasmin. 1
Molecular Function
Factor XIIIa cross-links the α- and γ-chains of fibrinogen to form α-polymers and γ-dimers, respectively, which stabilizes the fibrin polymer and renders it more refractory to degradation by plasmin 1
The enzyme catalyzes formation of ε-(γ-glutamyl)lysine isopeptide bonds between specific glutamine and lysine residues on adjacent fibrin molecules 2
Gamma-chain crosslinking occurs rapidly with high catalytic efficiency (kcat = 1872 min⁻¹, Km = 6.2 μM), while alpha-chain crosslinking proceeds much more slowly 3
Factor XIIIa also cross-links α₂-plasmin inhibitor to fibrin, which protects the clot from premature fibrinolysis 4
Position in Coagulation Cascade
Factor XIII functions in the terminal phase of the coagulation cascade, after thrombin has converted fibrinogen to fibrin 3, 4
Thrombin activates zymogen Factor XIII to Factor XIIIa in the presence of calcium ions 3
The enzyme acts on polymerized fibrin gel rather than soluble fibrinogen, requiring the fibrin network to be formed first 3
Clinical Implications
Bleeding Disorders
Congenital Factor XIII deficiency causes severe bleeding diathesis with impaired wound healing, intracranial hemorrhage, and recurrent miscarriages 1
Acquired Factor XIII deficiency (defined as <60% of normal plasma concentration) occurs with perioperative bleeding, postpartum hemorrhage, and after cardiopulmonary bypass 1
In cardiac surgery, Factor XIII levels decrease after CPB, and an inverse relationship exists between Factor XIII levels and postoperative blood loss 1
Thrombotic Disorders
Elevated Factor XIII levels represent a gender-specific risk factor for coronary artery disease and peripheral arterial disease in females only 4
During active thrombosis, Factor XIII activity and subunit "a" concentration decrease significantly due to consumption, with recovery to normal values occurring over approximately two weeks 5
The Factor XIII-A Val34Leu polymorphism provides moderate protection against coronary artery disease and venous thromboembolism based on meta-analyses 4
Therapeutic Considerations
Plasma-derived Factor XIII concentrate and recombinant Factor XIII (rFXIII) are available for supplementation in congenital deficiency 1
Despite theoretical benefits, Factor XIII supplementation (17.5-35 IU/kg) after cardiopulmonary bypass failed to reduce transfusion requirements or surgical re-exploration for bleeding in a randomized trial of 409 cardiac surgery patients 1
Factor XIII administration maintained clot firmness on viscoelastic assays but had minimal effect on actual blood loss in gastrointestinal surgery patients 1
Common Pitfalls
Do not use Factor XIII concentrates as routine prophylaxis for perioperative bleeding—the 2018 ISTH guidance suggests against this practice based on lack of efficacy in clinical trials 1
Factor XIII deficiency can exist despite normal PT, PTT, platelet counts, and fibrinogen levels, requiring specific Factor XIII activity measurement for diagnosis 1
In liver cirrhosis, both Factor XIII transamidase activity and subunit concentrations are decreased, emphasizing the need for Factor XIII substitution in these patients 6
Factor XIII inhibitors (such as tridegin from leeches) enhance fibrinolysis and represent potential antithrombotic agents, though none have been tested in humans 1