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Targeting anticoagulant protein S to improve hemostasis in hemophilia.

  • Prince R Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
  • Bologna L Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
  • Manetti M Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, and.
  • Melchiorre D Department of Experimental and Clinical Medicine, Section of Internal Medicine, Rheumatology Unit, Careggi University Hospital, University of Florence, Florence, Italy.
  • Rosa I Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, and.
  • Dewarrat N Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
  • Suardi S Vetsuisse, Institute of Animal Pathology, Comparative Pathology Platform, and.
  • Amini P Institute of Pharmacology, University of Bern, Bern, Switzerland.
  • Fernández JA Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA.
  • Burnier L Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA.
  • Quarroz C Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
  • Reina Caro MD Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
  • Matsumura Y Division of Developmental Therapeutics, Research Centre for Innovative Oncology, National Cancer Centre Hospital East, Chiba, Japan; and.
  • Kremer Hovinga JA Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
  • Griffin JH Department of Molecular and Experimental Medicine, Scripps Research Institute, La Jolla, CA.
  • Simon HU Institute of Pharmacology, University of Bern, Bern, Switzerland.
  • Ibba-Manneschi L Department of Experimental and Clinical Medicine, Section of Anatomy and Histology, and.
  • Saller F INSERM UMR-S 1176, Université Paris-Sud, Université Paris-Saclay, Le Kremlin-Bicêtre, France.
  • Calzavarini S Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
  • Angelillo-Scherrer A Department of Hematology and Central Hematology Laboratory, Inselspital, Bern University Hospital, and.
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  • 2018-01-11
Published in:
  • Blood. - 2018
Animals
Blood Coagulation
Carrier Proteins
Fibrin
Gene Silencing
Hemophilia A
Hemorrhage
Humans
Mice
Mice, Knockout
Thrombin
English Improved treatments are needed for hemophilia A and B, bleeding disorders affecting 400 000 people worldwide. We investigated whether targeting protein S could promote hemostasis in hemophilia by rebalancing coagulation. Protein S (PS) is an anticoagulant acting as cofactor for activated protein C and tissue factor pathway inhibitor (TFPI). This dual role makes PS a key regulator of thrombin generation. Here, we report that targeting PS rebalances coagulation in hemophilia. PS gene targeting in hemophilic mice protected them against bleeding, especially when intra-articular. Mechanistically, these mice displayed increased thrombin generation, resistance to activated protein C and TFPI, and improved fibrin network. Blocking PS in plasma of hemophilia patients normalized in vitro thrombin generation. Both PS and TFPIα were detected in hemophilic mice joints. PS and TFPI expression was stronger in the joints of hemophilia A patients than in those of hemophilia B patients when receiving on-demand therapy, for example, during a bleeding episode. In contrast, PS and TFPI expression was decreased in hemophilia A patients receiving prophylaxis with coagulation factor concentrates, comparable to osteoarthritis patients. These results establish PS inhibition as both controller of coagulation and potential therapeutic target in hemophilia. The murine PS silencing RNA approach that we successfully used in hemophilic mice might constitute a new therapeutic concept for hemophilic patients.
Language
  • English
Open access status
bronze
Identifiers
Persistent URL
https://sonar.ch/global/documents/89993
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