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

Jens Müller, D. Freitag, G. Mayer, Bernd Pötzsch

Research output: Contribution to journalArticle

71 Citations (Scopus)

Abstract

Background: HD1-22 is a bivalent aptamer that binds to thrombin with high affinity (K-d = 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.
LanguageEnglish
Pages2105-2112
Number of pages7
JournalJournal of Thrombosis and Haemostasis
Volume6
Issue number12
DOIs
Publication statusPublished - Dec 2008

Fingerprint

Thromboplastin
Thrombin
Anticoagulants
Antidotes
Oligodeoxyribonucleotides
Thrombin Time
Antithrombins
Partial Thromboplastin Time
Prothrombin
Platelet Aggregation
Anions
Enzymes
bivalirudin
argatroban

Keywords

  • HD1-22
  • prothrombinase
  • thrombin
  • activation
  • binding
  • molecules
  • ligands

Cite this

Müller, Jens ; Freitag, D. ; Mayer, G. ; Pötzsch, Bernd. / Anticoagulant characteristics of HD1-22, a bivalent aptamer that specifically inhibits thrombin and prothrombinase. In: Journal of Thrombosis and Haemostasis. 2008 ; Vol. 6, No. 12. pp. 2105-2112.
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Anticoagulant characteristics of HD1-22, a bivalent aptamer that specifically inhibits thrombin and prothrombinase. / Müller, Jens; Freitag, D.; Mayer, G.; Pötzsch, Bernd.

In: Journal of Thrombosis and Haemostasis, Vol. 6, No. 12, 12.2008, p. 2105-2112.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Anticoagulant characteristics of HD1-22, a bivalent aptamer that specifically inhibits thrombin and prothrombinase

AU - Müller, Jens

AU - Freitag, D.

AU - Mayer, G.

AU - Pötzsch, Bernd

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N2 - Background: HD1-22 is a bivalent aptamer that binds to thrombin with high affinity (K-d = 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.

AB - Background: HD1-22 is a bivalent aptamer that binds to thrombin with high affinity (K-d = 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.

KW - HD1-22

KW - prothrombinase

KW - thrombin

KW - activation

KW - binding

KW - molecules

KW - ligands

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DO - 10.1111/j.1538-7836.2008.03162.x

M3 - Article

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JF - Journal of Thrombosis and Haemostasis

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ER -