Coagulation factor XIII variants with altered thrombin activation rates.
Coagulation factor XIII (FXIII) is activated by thrombin and catalyses crosslinking between fibrin monomers thereby providing mechanical strength to the fibrin network. V34L is a common FXIII-A polymorphism found in the activation peptide. FXIII-A V34L is activated faster by thrombin and provides formation of a tighter clot at fibrinogen concentrations in the low end of the physiological range. FXIII-A variants with potentially increased activation rates were generated. Introduction of an optimal thrombin cleavage site, V34L+V35T, increased the activation rate 7.6-fold and facilitated the formation of a fibrin network more resistant to fibrinolysis than obtained with wt FXIII-A. In contrast, introduction of fragments of fibrinopeptide A into the activation peptide resulted in severely impaired activation rates.
Biopharmaceutical Research Unit, Novo Nordisk A/S, Novo Nordisk Park, DK-2760 Måløv, Denmark.
Mette Dahl
MD
Andersen
Marianne
M
Kjalke
Susanne
S
Bang
Inger
I
Lautrup-Larsen
Peter
P
Becker
Asser Sloth
AS
Andersen
Ole Hvilsted
OH
Olsen
Henning R
HR
Stennicke
D017398:Alternative Splicing; D000595:Amino Acid Sequence; D004789:Enzyme Activation; D005176:Factor XIII / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008958:Models, Molecular; D008969:Molecular Sequence Data; D020836:Protein Structure, Quaternary; D013917:Thrombin / Q000378:metabolism*
D005176:Factor XIII; D013917:Thrombin