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

Summary 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.