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F376A/M388A‐solulin, a new promising antifibrinolytic for severe haemophilia A
Author(s) -
Parcq J.,
Petersen K. U.,
BorelDerlon A.,
Gautier P.,
Ebel M.,
Vivien D.,
Repessé Y.
Publication year - 2017
Publication title -
haemophilia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.213
H-Index - 92
eISSN - 1365-2516
pISSN - 1351-8216
DOI - 10.1111/hae.13126
Subject(s) - fibrinolysis , medicine , haemophilia , thrombomodulin , coagulation , hyperfibrinolysis , haemophilia a , haemophilia b , antifibrinolytic , thromboelastography , thrombin , protein c , thrombelastography , immunology , pharmacology , surgery , tranexamic acid , platelet , blood loss
Introduction 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. Aim 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 n m ). Conclusion In sum, these results open new opportunities for the development of specific medication for haemophilic patients.