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

Judith Lahav, Ariella Tvito, Z. Bagoly, Rima Dardik, Aida Inbal

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Background 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. Objective This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity. Methods 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). Results 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 (10 IU/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%. Conclusion These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.

Original languageEnglish
Pages (from-to)338-341
Number of pages4
JournalThrombosis Research
Volume131
Issue number4
DOIs
Publication statusPublished - Apr 2013

Fingerprint

Protein Disulfide-Isomerases
Factor XIII
Fibrinogen
Blood Platelets
Fibrinolysin
Factor XIIIa
Iodoacetamide
Transglutaminases
Therapeutics
Fibrin
Platelet Aggregation
Thrombin
Microscopy

Keywords

  • Factor XIII
  • PDI
  • platelet adhesion
  • Transglutaminase

ASJC Scopus subject areas

  • Hematology

Cite this

Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity. / Lahav, Judith; Tvito, Ariella; Bagoly, Z.; Dardik, Rima; Inbal, Aida.

In: Thrombosis Research, Vol. 131, No. 4, 04.2013, p. 338-341.

Research output: Contribution to journalArticle

Lahav, Judith ; Tvito, Ariella ; Bagoly, Z. ; Dardik, Rima ; Inbal, Aida. / Factor XIII improves platelet adhesion to fibrinogen by protein disulfide isomerase-mediated activity. In: Thrombosis Research. 2013 ; Vol. 131, No. 4. pp. 338-341.
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abstract = "Background 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. Objective This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity. Methods 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). Results 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 (10 IU/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{\%}. Conclusion These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.",
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N2 - Background 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. Objective This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity. Methods 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). Results 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 (10 IU/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%. Conclusion These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.

AB - Background 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. Objective This study sought to examine possible mechanistic effect of FXIII on platelet adhesion to fibrinogen; specifically, the role of its PDI activity. Methods 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). Results 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 (10 IU/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%. Conclusion These findings indicate that FXIII-induced enhancement of platelet adhesion is mediated by FXIII-PDI activity.

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