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Novel insights into the regulation of coagulation by factor V isoforms, tissue factor pathway inhibitor α, and protein S
Author(s) -
Dahlbäck B.
Publication year - 2017
Publication title -
journal of thrombosis and haemostasis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.947
H-Index - 178
eISSN - 1538-7836
pISSN - 1538-7933
DOI - 10.1111/jth.13665
Subject(s) - tissue factor pathway inhibitor , prothrombinase , gene isoform , tissue factor , microbiology and biotechnology , thrombin , chemistry , factor v , factor x , protein c , coagulation , cofactor , biochemistry , plasma protein binding , biology , platelet , immunology , enzyme , gene , medicine , thrombosis
Summary Factor V ( FV ) is a regulator of both pro‐ and anticoagulant pathways. It circulates as a single‐chain procofactor, which is activated by thrombin or FX a to FV a that serves as cofactor for FX a in prothrombin activation. The cofactor function of FV a is regulated by activated protein C ( APC ) and protein S. FV can also function as an anticoagulant APC cofactor in the inhibition of FVIII a in the membrane‐bound tenase complex ( FIX a/ FVIII a). In recent years, it has become clear that FV also functions in multiple ways in the tissue factor pathway inhibitor ( TFPI ) anticoagulant pathway. Of particular importance is a FV splice variant ( FV ‐Short) that serves as a carrier and cofactor to TFPI α in the inhibition of FX a. FV ‐Short is generated through alternative splicing of exon 13 that encodes the large activation B domain. A highly negatively charged binding site for TFPI α is exposed in the C‐terminus of the FV ‐Short B domain, which binds the positively charged C‐terminus of TFPI α , thus keeping TFPI α in circulation. The binding of TFPI α to FV ‐Short is also instrumental in localizing the inhibitor to the surface of negatively charged phospholipids, where TFPI α inhibits FX a in process that is stimulated by protein S. Plasma FV activation intermediates and partially proteolyzed platelet FV similarly bind TFPI α with high affinity and regulate formation of prothrombinase. The novel insights gained into the interaction between FV isoforms, TFPI α, and protein S have opened a new avenue for research about the mechanisms of coagulation regulation and also for future development of therapeutics aimed at modulating coagulation.