PMID- 35445541
OWN - NLM
STAT- MEDLINE
DCOM- 20220628
LR  - 20230829
IS  - 1538-7836 (Electronic)
IS  - 1538-7836 (Linking)
VI  - 20
IP  - 7
DP  - 2022 Jul
TI  - Antithrombotic potential of a single-domain antibody enhancing the activated 
      protein C-cofactor activity of protein S.
PG  - 1653-1664
LID - 10.1111/jth.15736 [doi]
AB  - BACKGROUND: Protein S (PS) is a natural anticoagulant acting as a cofactor for 
      activated protein C (APC) in the proteolytic inactivation of activated factors V 
      (FVa) and VIII (FVIIIa), but also for tissue factor pathway inhibitor alpha (TFPIalpha) 
      in the inhibition of activated factor X (FXa). OBJECTIVE: For therapeutic 
      purposes, we aimed at generating single-domain antibodies (sdAbs) that could 
      specifically modulate the APC-cofactor activity of PS in vivo. METHODS: A 
      llama-derived immune library of sdAbs was generated and screened on recombinant 
      human PS by phage display. PS binders were tested in a global activated partial 
      thromboplastin time (APTT)-based APC-cofactor activity assay. RESULTS: A 
      PS-specific sdAb (PS003) was found to enhance the APC-cofactor activity of PS in 
      our APTT-based assay, and this enhancing effect was greater for a bivalent form 
      of PS003 (PS003biv). Further characterization of PS003biv demonstrated that 
      PS003biv also enhanced the APC-cofactor activity of PS in a tissue factor 
      (TF)-induced thrombin generation assay and stimulated APC in the inactivation of 
      FVa, but not FVIIIa, in plasma-based assays. Furthermore, PS003biv was directed 
      against the sex hormone-binding globulin (SHBG)-like domain but did not inhibit 
      the binding of PS to C4b-binding protein (C4BP) and did not interfere with the 
      TFPIalpha-cofactor activity of PS. In mice, PS003biv exerted an antithrombotic effect 
      in a FeCl(3) -induced thrombosis model, while not affecting physiological 
      hemostasis in a tail-clip bleeding model. DISCUSSION: Altogether, these results 
      showed that pharmacological enhancement of the APC-cofactor activity of PS 
      through an original anti-PS sdAb might constitute a promising and safe 
      antithrombotic strategy.
CI  - (c) 2022 International Society on Thrombosis and Haemostasis.
FAU - Sedzro, Josepha C
AU  - Sedzro JC
AUID- ORCID: 0000-0001-6577-3029
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Adam, Frederic
AU  - Adam F
AUID- ORCID: 0000-0001-6603-2687
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Auditeau, Claire
AU  - Auditeau C
AUID- ORCID: 0000-0002-8499-1862
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
AD  - Service d'Hematologie Biologique, Hopital Necker Enfants Malades, Assistance 
      Publique-Hopitaux de Paris (AP-HP), Paris, France.
FAU - Bianchini, Elsa
AU  - Bianchini E
AUID- ORCID: 0000-0002-1370-5312
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - De Carvalho, Allan
AU  - De Carvalho A
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Peyron, Ivan
AU  - Peyron I
AUID- ORCID: 0000-0002-3843-642X
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Darame, Sadyo
AU  - Darame S
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Gandrille, Sophie
AU  - Gandrille S
AD  - Innovations Therapeutiques en Hemostase, UMR-S1140, INSERM, Universite de Paris, 
      Paris, France.
AD  - Service d'Hematologie Biologique, Hopital Europeen Georges Pompidou, Assistance 
      Publique-Hopitaux de Paris (AP-HP), Paris, France.
FAU - Thomassen, Stella
AU  - Thomassen S
AUID- ORCID: 0000-0002-9686-6364
AD  - Cardiovascular Research Institute Maastricht (CARIM), University Maastricht, 
      Maastricht, the Netherlands.
FAU - Hackeng, Tilman M
AU  - Hackeng TM
AD  - Cardiovascular Research Institute Maastricht (CARIM), University Maastricht, 
      Maastricht, the Netherlands.
FAU - Christophe, Olivier D
AU  - Christophe OD
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Lenting, Peter J
AU  - Lenting PJ
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Denis, Cecile V
AU  - Denis CV
AUID- ORCID: 0000-0001-5152-9156
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
FAU - Borgel, Delphine
AU  - Borgel D
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
AD  - Service d'Hematologie Biologique, Hopital Necker Enfants Malades, Assistance 
      Publique-Hopitaux de Paris (AP-HP), Paris, France.
FAU - Saller, Francois
AU  - Saller F
AUID- ORCID: 0000-0001-5255-2630
AD  - Hemostase, Inflammation, Thrombose (HITh), UMR-S1176, INSERM, Universite 
      Paris-Saclay, Le Kremlin-Bicetre, France.
LA  - eng
PT  - Journal Article
DEP - 20220502
PL  - England
TA  - J Thromb Haemost
JT  - Journal of thrombosis and haemostasis : JTH
JID - 101170508
RN  - 0 (Fibrinolytic Agents)
RN  - 0 (Protein C)
RN  - 0 (Protein S)
RN  - 0 (Single-Domain Antibodies)
RN  - 72175-66-7 (Factor VIIIa)
SB  - IM
MH  - Animals
MH  - Factor VIIIa/chemistry
MH  - Fibrinolytic Agents/pharmacology
MH  - Humans
MH  - Mice
MH  - Protein C/metabolism
MH  - *Protein S/metabolism
MH  - *Single-Domain Antibodies
OTO - NOTNLM
OT  - blood coagulation
OT  - protein C
OT  - protein S
OT  - single-domain antibodies
OT  - thrombosis
EDAT- 2022/04/22 06:00
MHDA- 2022/06/29 06:00
CRDT- 2022/04/21 05:49
PHST- 2022/04/05 00:00 [revised]
PHST- 2021/11/23 00:00 [received]
PHST- 2022/04/19 00:00 [accepted]
PHST- 2022/04/22 06:00 [pubmed]
PHST- 2022/06/29 06:00 [medline]
PHST- 2022/04/21 05:49 [entrez]
AID - S1538-7836(22)01927-4 [pii]
AID - 10.1111/jth.15736 [doi]
PST - ppublish
SO  - J Thromb Haemost. 2022 Jul;20(7):1653-1664. doi: 10.1111/jth.15736. Epub 2022 May 
      2.