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Targeting Protease Nexin-1, a Natural Anticoagulant, to Control Bleeding in Hemophilia A
ISTH Academy. Aymonnier K. Jul 10, 2019; 273874; OC 75.3
Karen Aymonnier
Karen Aymonnier
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OC 75.3

Targeting Protease Nexin-1, a Natural Anticoagulant, to Control Bleeding in Hemophilia A

K. Aymonnier1, C. Kawecki2, L. Venisse1, E. De Raucourt3, O. Christophe2, P. Lenting2, V. Arocas1, C. Denis1, M.-C. Bouton1
1INSERM, U 1148, Paris, France, 2INSERM, U 1176, Le Kremlin Bicêtre, France, 3Hôpital Beaujon, Service Hématologie Biologique, Clichy, France

Main Topic: Hemophilia and Bleeding (including Transfusion)
Category: Hemophilia - Basic

Background: Hemophilia is a disease caused by the lack of Factor VIII (FVIII) or Factor IX (FIX), leading to insufficient thrombin production, and therefore bleeding. Recently, new therapeutic strategies for hemophilia treatment, that do not rely on clotting factor replacement, have emerged,.
Aims: We propose an innovative approach consisting in targeting a natural and potent thrombin inhibitor, expressed by platelets and called Protease Nexin-1 (PN-1).
Methods: We used the calibrated automated thrombogram (CAT) assay to test the effect of a PN-1 neutralizing antibody, on thrombin generation in platelet-rich plasma (PRP) of hemophiliac patients. CAT assay was also performed on PRP from haemophilia A (HA mice), wild-type, and double knockout mice for PN-1 and FVIII (dKO mice). Thromboelastometry study (ROTEM®) was carried out on murine whole blood to evaluate clot fibrinolysis. Different in vivo studies : i) arterial and venous bleeding time, ii) monitoring of mesenteric vessel occlusion after ferric chloride-induced thrombosis, were performed in mice.
Results: The PN-1 neutralizing antibody increases thrombin generation in response to tissue factor, in PRP from patients displaying circulating FVIII greater than 1%. In contrast, PN-1 neutralization improves thrombin generation neither in PRP from severe hemophilia patients nor in PRP from HA mice. However, PN-1-deficiency can improve significantly thrombin generation in PRP from HA mice, after collagen-induced platelet activation. ROTEM® results show increased clot stability and clot lysis time in blood from DKO mice compared with HA mice.
In both bleeding time models, dKO mice display significant reduced blood loss and bleeding time compared to HA mice. Following ferric-chloride-induced injury of mesenteric vessels, platelet recruitment and fibrin(ogen) accumulation are significantly higher in DKO mice than in HA mice.
Conclusions: Our study provides proof-of-concept that PN-1 neutralizing can be a a novel approach for future clinical care in hemophilia.

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