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Deprecated: Implicit conversion from float 213.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Res+Pract+Thromb+Haemost 2018 ; 2 (1): 114-24 Nephropedia Template TP
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Factor V?short and protein S as synergistic tissue factor pathway inhibitor (TFPI?) cofactors #MMPMID30046712
Dahlbäck B; Guo LJ; Livaja?Koshiar R; Tran S
Res Pract Thromb Haemost 2018[Jan]; 2 (1): 114-24 PMID30046712show ga
Essentials: FV?Short, a normal splice isoform of Factor V, binds tissue factor pathway inhibitor (TFPI?) with high affinity.FV?Short functions as a synergistic TFPI? cofactor with protein S in inhibition of Factor Xa.FV?Short is much more efficient as TFPI? cofactor than full length FV.TFPI??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 ? (TFPI?). FV?Short and TFPI? circulate in complex in plasma. Objectives: The aim was to elucidate whether FV?Short affects TFPI? as inhibitor of coagulation FXa and to test whether the TFPI??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 FXa inhibitory activity of TFPI? was monitored both in a purified system and in a plasma?based thrombin generation assay. Results: FV?Short had intrinsically weak TFPI??cofactor activity but with protein S present, FV?Short yielded efficient inactivation of FXa. Protein S alone did not promote full TFPI??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??cofactor activity. The synergistic TFPI??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? in the regulation of FXa activity, whereas full length FV has lower activity. Our results suggest the formation of an efficient FXa?inhibitory complex between FV?Short, TFPI? and protein S on the surface of negatively charged phospholipids.