Abstract
Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-of-care parenteral anticoagulants for percutaneous coronary intervention (PCI). We discovered novel direct thrombin inhibitors (DTIs) from tick salivary transcriptomes and optimised their pharmacologic activity. The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin. Unexpectedly, despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Moreover, two antibodies screened from a naïve human antibody library effectively reversed the anticoagulant activity of ultravariegin, demonstrating proof-of-principle for antidote reversal. Variegin and ultravariegin are promising translational candidates for next-generation DTIs that may reduce peri-PCI bleeding in the presence of antiplatelet therapy.
Highlights
Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-ofcare parenteral anticoagulants for percutaneous coronary intervention (PCI)
Bivalirudin is more expensive (~$400 to $600 per PCI without post-procedural infusion5), initial randomised trials showed that bivalirudin was associated with similar antithrombotic efficacy but less bleeding when compared with a combination of UFH and a platelet glycoprotein IIb/IIIa inhibitor[8,9,10]
Variegin-like thrombin inhibitors in Amblyomminae are synthesised as larger precursor proteins containing multiple repeats that are post-translationally processed into shorter peptides[30]
Summary
Despite their limitations, unfractionated heparin (UFH) and bivalirudin remain standard-ofcare parenteral anticoagulants for percutaneous coronary intervention (PCI). The most potent, ultravariegin, inhibits thrombin with a Ki of 4.0 pM, 445-fold better than bivalirudin Despite their greater antithrombotic effect, variegin/ultravariegin demonstrated less bleeding, achieving a 3-to-7-fold wider therapeutic index in rodent thrombosis and bleeding models. When used in combination with aspirin and ticagrelor in a porcine model, variegin/ultravariegin reduced stent thrombosis compared with antiplatelet therapy alone but achieved a 5-to-7-fold lower bleeding time than UFH/bivalirudin. Bivalirudin is more expensive (~$400 to $600 per PCI without post-procedural infusion5), initial randomised trials showed that bivalirudin was associated with similar antithrombotic efficacy but less bleeding when compared with a combination of UFH and a platelet glycoprotein IIb/IIIa inhibitor[8,9,10].
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