The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis

Shu He; Margareta Blombäck; Niklas Bark; Hans Johnsson; N. Hakan Wallen

doi:10.1160/TH09-05-0306

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2010; 103(05): 1076-1084
DOI: 10.1160/TH09-05-0306

New Technologies, Diagnostic Tools and Drugs

Schattauer GmbH

The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis

Shu He

¹Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

²Department of Molecular Medicine & Surgery (Coagulation), Karolinska Institutet, Stockholm, Sweden

,

Margareta Blombäck

¹Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

²Department of Molecular Medicine & Surgery (Coagulation), Karolinska Institutet, Stockholm, Sweden

,

Niklas Bark

²Department of Molecular Medicine & Surgery (Coagulation), Karolinska Institutet, Stockholm, Sweden

³Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden

,

Hans Johnsson

⁴Department of Medicine at Karolinska University Hospital, Stockholm, Sweden

,

N. Hakan Wallen

¹Department of Clinical Sciences, Danderyd Hospital, Karolinska Institutet, Stockholm, Sweden

› Author Affiliations

Abstract

Summary

The present study aimed to assess whether the fibrin network structure is modified by the direct thrombin-inhibitors lepirudin, argatroban or bivalirudin and by the indirect Xa-inhibitor danaparoid. Using an in vitro assay that imitates the physiological process of coagulation from thrombin generation to fibrin formation, we examined a normal plasma pool spiked with one of the inhibitors. At concentrations considered to be the plasma levels observed during therapy, almost no influence was detected for lepirudin despite clear-cut effects on “clotting time”. However, argatroban, bivalirudin and danaparoid increased the fibrin gel permeability (Ks) to a similar extent. At concentrations higher than the “therapeutic” levels, the dose-response curve in the Ks assay became very steep for lepirudin while those were shallow for the others. In parallel with the drug-induced increases of Ks, larger network pores in 3D-microscopic images and significant shortenings in “clot lysis time” induced by addition of rtPA were observed. Recombinant factor VIII (rFVIII) added to danaparoid-treated samples profoundly counteracted the increase of Ks but had only a slight or no effect on the other drugs. Thus, in vitro, argatroban, bivalirudin and danaparoid have comparable anticoagulating effects, rendering the fibrin network more permeable and less resistant to fibrinolysis. For lepirudin, the steep dose-response curve supports previous clinical findings, i.e. this thrombin inhibitor has a narrow therapeutic window. Furthermore, our data suggest that the haemostatic agent, rFVIII, might be effective in treatment of bleeding complications induced by danaparoid.

Keywords

Thrombin inhibitor - factor-Xa inhibitor - fibrin network porosity - fibrinolysis - recombinant FVIII

Full Text

References

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