Free factor XIII activation peptide (fAP-FXIII) is a regulator of factor XIII activity via factor XIII-B

Abstract

In a factor XIIIa (FXIIIa) generation assay with recombinant FXIII-A2 (rFXIII-A2) free FXIII activation peptide (fAP-FXII) prolonged the time to peak (TTP) but did not affect the area under the curve (AUC) or concentration at peak (CP). Addition of recombinant factorXIII-B2 (rFXIII-B2) restored the characteristics of the FXIIIa generation parameters (AUC, TTP and CP) to those observed for plasma FXIII (FXIII-A2B2). FXIII-A2B2 reconstituted from rFXIII-A2 and rFXIII-B2 showed a similar effect on AUC, TTP and CP in the presence of fAP-FXII as observed for plasma FXIII-A2B2, indicating a role for FXIII-B in this observation. An effect of fAP-FXIII on thrombin, the proteolytic activator of FXIII, was excluded by thrombin generation assays and clotting experiments. In a purified system, fAP-FXIII did not interfere with the FXIIIa activity development of thrombin-cleaved rFXIII-A2 (rFXIII-A2′) also excluding direct inhibition of FXIIIa. However, FXIIIa activity development of FXIII-A2′B2 was inhibited in a concentration-dependent manner by fAP-FXIII, indicating that an interaction between AP-FXIII and FXIII-B2 contributes to the overall stability of FXIII-A2′B2. In addition to its well-known role, FXIII-B also contributes to FXIII-A2B2 stability or dissociation depending on fAP-FXIII and calcium concentrations.