Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity

Factor XIII (FXIII), a plasma pro-transglutaminase, consists of two A subunits and two B subunits (FXIIIA2B2). Following activation by thrombin, it cross-links fibrin chains at the final step of coagulation. We previously reported that FXIII subunit A (FXIIIA) serves as a protein disulfide isomerase (PDI), and that PDI promotes platelet adhesion and aggregation.

This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity.

Ex vivo experiments: Blood platelets derived from five patients with hereditary FXIIIA deficiency before and after treatment with Fibrogammin-P (FXIIIA2B2 concentrate) were washed and incubated on immobilized fibrinogen. Bound platelets were stained and counted by microscopy. In vitro experiments: Platelets derived from patients before treatment and five healthy controls were washed and analyzed for adhesion in the presence or absence of Fibrogammin-P or recombinant FXIII (FXIIIA2 concentrate).

In ex vivo experiments, one hour after Fibrogammin-P treatment, mean (±SEM) platelet adhesion to fibrinogen increased by 27±2.32% (p<0.001). In in vitro experiments, treatment with Fibrogammin-P or recombinant FXIII (10IU/mL each) enhanced platelet adhesion to fibrinogen (in patients, by 29.95±6.7% and 29.05±5.3%, respectively; in controls, by 26.06±3.24% and 26.91±4.72, respectively; p<0.04 for all). Iodoacetamide-treated FXIII (I-FXIII), where transglutaminase activity is blocked, showed similar enhanced adhesion as untreated FXIII. By contrast, addition of an antibody that specifically blocks FXIIIA-PDI activity inhibited FXIII-mediated platelet adhesion to fibrinogen by 65%.

These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.