Anticoagulant characteristics of HD1‐22, a bivalent aptamer that specifically inhibits thrombin and prothrombinase

• Published in: Journal of thrombosis and haemostasis Vol. 6; no. 12; pp. 2105 - 2112
• Main Authors: MÜLLER, J., FREITAG, D., MAYER, G., PÖTZSCH, B.
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2008
• Subjects: Anticoagulants - pharmacology; Aptamers, Nucleotide - pharmacology; Aptamers, Nucleotide - therapeutic use; Blood Coagulation - drug effects; Dose-Response Relationship, Drug; HD1‐22; Humans; Platelet Aggregation - drug effects; prothrombinase; thrombin; Thrombin - antagonists & inhibitors; Thromboplastin - antagonists & inhibitors
• ISSN: 1538-7933; 1538-7836; 1538-7836
• DOI: 10.1111/j.1538-7836.2008.03162.x

Background: HD1‐22 is a bivalent aptamer that binds to thrombin with high affinity (Kd = 0.65 nm) and occupies both anion binding exosites without blocking the active centre of the enzyme. HD1‐22 has been developed by connecting the exosite 1 binding aptamer HD1 and the exosite 2 binding aptamer HD22 through a poly‐dA linker. Objectives: To characterize the anticoagulant profile of HD1‐22 in comparison to the clinically established direct acting thrombin inhibitors bivalirudin and argatroban, and to test the efficacy of antidote‐oligodeoxynucleotides. Methods and Results: HD1‐22 prolongs clotting times of the thrombin time, activated partial thromboplastin time, ecarin clotting time, and lag‐time of the tissue factor triggered thrombin generation assay in a dose‐dependent manner. On a molar basis, its anticoagulant activity was nearly identical to bivalirudin and superior to argatroban. Thrombin‐induced platelet aggregation was more effectively inhibited by HD1‐22 than by bivalirudin. The HD1‐22 aptamer retains the ability of the HD1‐moiety to bind to (pro)exosite 1 of prothrombin and inhibits the prothrombinase activity nearly 2‐fold better than HD1. The anticoagulant activities of HD1‐22 are fully reversed by addition of antidote‐oligodeoxynucleotides. Conclusions: The strong thrombin‐inhibiting activity, together with the availability of a rapid acting antidote strategy, makes HD1‐22 an interesting anticoagulant candidate, especially for use in clinical situations where effective anticoagulation and rapid reversal of the anticoagulant effect are required. The data obtained warrant further clinical studies.