title: Solulin increases clot stability in whole blood from humans and dogs with hemophilia.
abstract: Solulin is a soluble form of thrombomodulin that is resistant to proteolysis and oxidation. It has been shown to increase the clot lysis time in factor VIII (fVIII)-deficient plasma by an activated thrombin-activatable fibrinolysis inhibitor (TAFIa)-dependent mechanism. In the present study, blood was drawn from humans and dogs with hemophilia, and thromboelastography was used to measure tissue factor-initiated fibrin formation and tissue-plasminogen activator-induced fibrinolysis. The kinetics of TAFI and protein C activation by the thrombin-Solulin complex were determined to describe the relative extent of anticoagulation and antifibrinolysis. In severe hemophilia A, clot stability increased by > 4-fold in the presence of Solulin while minimally affecting clot lysis time. Patients receiving fVIII/fIX prophylaxis showed a similar trend of increased clot stability in the presence of Solulin. The catalytic efficiencies of TAFI and protein C activation by the thrombin-Solulin complex were determined to be 1.53 and 0.02/μM/s, respectively, explaining its preference for antifibrinolysis over anticoagulation at low concentrations. Finally, hemophilic dogs given Solulin had improved clot strength in thromboelastography assays. In conclusion, the antifibrinolytic properties of Solulin are exhibited in hemophilic human (in vitro) and dog (in vivo/ex vivo) blood at low concentrations. Our findings suggest the therapeutic utility of Solulin at a range of very low doses.
authors.affiliation: Haemostasis Research Unit, Centre for Haemostasis & Thrombosis, Guy's & St Thomas' National Health Service Foundation Trust, St Thomas' Hospital, London, UK. jonathan.foley@uvm.edu
authors.forename: Jonathan H
authors.initials: JH
authors.lastname: Foley
authors.forename: Karl-Uwe
authors.initials: KU
authors.lastname: Petersen
authors.forename: Catherine J
authors.initials: CJ
authors.lastname: Rea
authors.forename: Lori
authors.initials: L
authors.lastname: Harpell
authors.forename: Sandra
authors.initials: S
authors.lastname: Powell
authors.forename: David
authors.initials: D
authors.lastname: Lillicrap
authors.forename: Michael E
authors.initials: ME
authors.lastname: Nesheim
authors.forename: Benny
authors.initials: B
authors.lastname: Sørensen
mesh_terms: D000328:Adult; D000818:Animals; D001777:Blood Coagulation / Q000187:drug effects*; D004283:Dog Diseases / Q000097:blood* / Q000188:drug therapy; D004285:Dogs; D005342:Fibrinolysis / Q000187:drug effects; D006467:Hemophilia A / Q000097:blood* / Q000188:drug therapy; D006801:Humans; D008875:Middle Aged; D059748:Proteolysis / Q000187:drug effects; D018179:Receptors, Thrombin / Q000627:therapeutic use; D011994:Recombinant Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D013997:Time Factors; D015854:Up-Regulation / Q000187:drug effects; D014914:Whole Blood Coagulation Time; D055815:Young Adult
chemical_list: D018179:Receptors, Thrombin; D011994:Recombinant Proteins; C558438:solulin protein