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Essentials    FV‐Short, a normal splice isoform of Factor V, binds tissue factor pathway inhibitor (TFPIα) with high affinity.  FV‐Short functions as a synergistic TFPIα cofactor with protein S in inhibition of Factor Xa.  FV‐Short is much more efficient as TFPIα cofactor than full length FV.  TFPIα‐cofactor activity of FV‐Short is lost upon activation of coagulation by thrombin‐mediated cleavage.Background   FV ‐Short is a normal splice variant of Factor V ( FV ) having a short B domain, which exposes a high affinity‐binding site for tissue factor pathway inhibitor α ( TFPI α).  FV ‐Short and  TFPI α circulate in complex in plasma.    Objectives  The aim was to elucidate whether  FV ‐Short affects  TFPI α as inhibitor of coagulation  FX a and to test whether the  TFPI α‐cofactor activity of protein S is influenced by  FV ‐Short.    Methods  Recombinant  FV , wild‐type  FV ‐Short and a  FV ‐Short thrombin‐cleavage resistant variant were expressed and purified. The influence of  FV  and  FV ‐Short variants and/or protein S on the  FX a inhibitory activity of  TFPI α was monitored both in a purified system and in a plasma‐based thrombin generation assay.    Results   FV ‐Short had intrinsically weak  TFPI α‐cofactor activity but with protein S present,  FV ‐Short yielded efficient inactivation of  FX a. Protein S alone did not promote full  TFPI α‐activity. Intact  FV  was inefficient at low protein S concentrations and had 10‐fold lower activity compared to  FV ‐Short at physiological protein S levels. Activation of  FV ‐Short by thrombin resulted in the loss of the  TFPI α‐cofactor activity. The synergistic  TFPI α‐cofactor activity of  FV ‐Short and protein S was also demonstrated in plasma using a thrombin generation assay.    Conclusions   FV ‐Short and protein S are highly efficient, synergistic cofactors to  TFPI α in the regulation of  FX a activity, whereas full length  FV  has lower activity. Our results suggest the formation of an efficient  FX a‐inhibitory complex between  FV ‐Short,  TFPI α and protein S on the surface of negatively charged phospholipids.

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor ( TFPI α) cofactors