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Bleeding complications limits the use of effective antithrombotics therapeutics. Here, the authors developed next-generation direct thrombin inhibitors with low bleeding risks as safe peri-percutaneous coronary intervention anticoagulants when used in combination with antiplatelets.

The mechanisms by which platelets release sphingosine-1-phosphate (S1P) is not well characterized. Here the authors show that Mfsd2b is required for S1P release from both resting and activated platelets and that deletion of Mfsd2b impairs thrombotic functions of platelets.

Activated factor XI (FXIa) is an important antithrombotic drug target. Clinical and pre-clinical data have demonstrated that its inhibition attenuates thrombosis with minimal risk of excessive bleeding. We isolated Fasxiator from the venom of banded krait Bungarus fasciatus and subsequently engineered FasxiatorN17R,L19E, with improved affinity (Ki = 0.9 nM) and selectivity towards FXIa. Here, we assess the in vivo efficacy and bleeding risk of rFasxiatorN17R, L19E in pre-clinical animal models. Rats injected intravenously (i.v.) with bolus rFasxiatorN17R, L19E showed the specific in vivo attenuation of the intrinsic coagulation pathway, lasting for at least 60 min. We performed the in vivo dose-ranging experiments for rFasxiatorN17R, L19E as follows: FeCl3-induced carotid artery occlusion in rats (arterial thrombosis); inferior vena cava ligation in mice (venous thrombosis); tail bleeding time in both rats and mice (bleeding risk). Head-to-head comparisons were made using therapeutic dosages of unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) for arterial and venous thrombosis, respectively. In the arterial thrombosis model, 2 mg/kg i.v. rFasxiatorN17R,L19E achieved a similar antithrombotic efficacy to that of UFH, with >3-fold lower bleeding time. In the venous thrombosis model, the 10 mg/kg subcutaneous (s.c.) injection of rFasxiatorN17R,L19E achieved similar efficacy and bleeding levels to those of LMWH enoxaparin. Overall, rFasxiatorN17R,L19E represents a promising molecule for the development of FXIa-targeting anticoagulants.