Targeting anticoagulant protein S to improve hemostasis in hemophilia

Targeting anticoagulant protein S to improve hemostasis in hemophilia
Current therapy for hemophilia involves replacement of the missing coagulation factor, which has numerous drawbacks including frequent IV infusions and risk of inhibitor formation. Newer approaches have explored gene therapy, antibody-based mimetic therapy, and targeting of coagulation inhibitors to restore thrombin generation. Protein S is a co-factor to activated protein C and tissue factor pathway inhibitor (TFPI), and is therefore a key regulator of thrombin generation.
A protein S (ProS) knockout mouse model was used to evaluate the potential role of protein S inhibition in management of hemophilia. This model was interbred with Factor 8 (F8) and Factor 9 (F9) knockout mice to generate mice which were co-deficient in either F8 or F9 and ProS. These mice were then studied in several bleeding models, including tail clipping and acute hemarthrosis, as well as a model of tissue factor-induced pulmonary embolism.
The model demonstrated that the loss of thrombin generation from F8 or F9 deficiency rescued the ProS deficient mice from thromboembolic complications, although it did not prevent induced pulmonary embolism. Tail bleeding was limited but not completely abrogated in F8 and ProS deficient mice, although ProS deficient mice with F8 or F9 deficiency were protected from acute hemarthrosis. Subsequent studies demonstrated that both ProS and TFPI are expressed in the synovium of both mice and human patients, which may explain this effect. As a final human proof of concept, the research group demonstrated that ProS inhibition in plasma restored thrombin generation in patients with F8 deficiency.
As an animal study, this requires further evaluation in human clinical trials.
Targeting ProS can improve hemophilia in a mouse model, both as an improved bleeding phenotype and protection against hemarthrosis. This may lead to the development of novel therapies for patients with hemophilia.