title: F376A/M388A-solulin, a new promising antifibrinolytic for severe haemophilia A.
abstract: BACKGROUND
  Haemophilia is a major bleeding disorder due to a deficiency of procoagulant factor VIII (type A) or IX (type B). The treatment is substitutive and based on infusion of factor concentrates. Main limitations of this therapy are cost, short factor half-life and the development of inhibitors (up to 30% of severe HA patients). An important aggravating factor of haemophilia is due to a premature fibrinolysis, directing attention to the therapeutic potential of suitable antifibrinolytics. Thrombomodulin (TM) is a key player of the coagulation cascade by activating protein C (an inhibitor of thrombin generation, thus antagonizing coagulation) and of the fibrinolytic cascade by activating thrombin activatable fibrinolysis inhibitor TAFI (thus reducing fibrinolysis). Solulin is a soluble form of TM that shows both capabilities.
  
  
  OBJECTIVE
  Here, we developed a new generation of solulin variants (F376A-, M388A- and F376A/M388A-solulin) with a decreased ability to activate protein C and a conserved capacity to activate TAFI.
  
  
  METHODS
  We produced and characterized solulin variants in vitro. In addition, F376A/M388A-solulin was tested ex vivo, using blood samples of haemophilic A patients, with thromboelastography.
  
  
  RESULTS
  The solulin variants (F376A, M388A and the double-mutant F376A/M388A) lost their abilities to activate protein C but are still capable to activate TAFI. Thrombelastography showed increased clot firmness and stability, that, as opposed to wild-type solulin, was maintained even at high concentrations of F376A/M388A-solulin (100 nm).
  
  
  CONCLUSIONS
  In sum, these results open new opportunities for the development of specific medication for haemophilic patients.
authors.affiliation: Serine Proteases and Pathophysiology of the Neurovascular Unit, Normandie Univ, UNICAEN, INSERM, Caen, France.
authors.forename: J
authors.initials: J
authors.lastname: Parcq
authors.affiliation: PAION Deutchland GmbH, Aachen, Germany.
authors.forename: K U
authors.initials: KU
authors.lastname: Petersen
authors.affiliation: Serine Proteases and Pathophysiology of the Neurovascular Unit, Normandie Univ, UNICAEN, INSERM, Caen, France.|Laboratoire d'hématologie, CHU de Caen, Caen, France.|Centre de Traitement de l'Hémophilie (CRTH), CHU de Caen, Caen, France.
authors.forename: A
authors.initials: A
authors.lastname: Borel-Derlon
authors.affiliation: Laboratoire d'hématologie, CHU de Caen, Caen, France.|Centre de Traitement de l'Hémophilie (CRTH), CHU de Caen, Caen, France.
authors.forename: P
authors.initials: P
authors.lastname: Gautier
authors.affiliation: PAION Deutchland GmbH, Aachen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Ebel
authors.affiliation: Serine Proteases and Pathophysiology of the Neurovascular Unit, Normandie Univ, UNICAEN, INSERM, Caen, France.
authors.forename: D
authors.initials: D
authors.lastname: Vivien
authors.affiliation: Serine Proteases and Pathophysiology of the Neurovascular Unit, Normandie Univ, UNICAEN, INSERM, Caen, France.|Laboratoire d'hématologie, CHU de Caen, Caen, France.|Centre de Traitement de l'Hémophilie (CRTH), CHU de Caen, Caen, France.
authors.forename: Y
authors.initials: Y
authors.lastname: Repessé
mesh_terms: D005169:Factor VIII / Q000627:therapeutic use*; D005342:Fibrinolysis / Q000502:physiology; D006467:Hemophilia A / Q000188:drug therapy*; D006801:Humans
chemical_list: D005169:Factor VIII
keywords: antifibrinolytic; haemophilia A; solulin