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

SHU HE ; BLOMBÄCK, Margareta ; BARK, Niklas ; JOHNSSON, Hans ; WALLEN, N. Hakan

Thrombosis and haemostasis, 2010-05, Vol.103 (5), p.1076-1084 [Periódico revisado por pares]

Stuttgart: Schattauer Verlag für Medizin und Naturwissenschaften

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Título:
The direct thrombin inhibitors (argatroban, bivalirudin and lepirudin) and the indirect Xa-inhibitor (danaparoid) increase fibrin network porosity and thus facilitate fibrinolysis
Autor: SHU HE ; BLOMBÄCK, Margareta ; BARK, Niklas ; JOHNSSON, Hans ; WALLEN, N. Hakan
Assuntos: Antithrombins - pharmacology ; Biological and medical sciences ; Blood coagulation. Blood cells ; Chondroitin Sulfates - pharmacology ; Chromatography, Gel ; Dermatan Sulfate - pharmacology ; Factor VIII - metabolism ; Factor Xa Inhibitors ; factor-Xa inhibitor ; Fibrin - chemistry ; Fibrin - metabolism ; fibrin network porosity ; fibrinolysis ; Fibrinolysis - drug effects ; Fundamental and applied biological sciences. Psychology ; Hematologic and hematopoietic diseases ; Heparinoids - pharmacology ; Heparitin Sulfate - pharmacology ; Hirudins - pharmacology ; Humans ; In Vitro Techniques ; Medical sciences ; Microscopy, Confocal ; Molecular and cellular biology ; New Technologies, Diagnostic Tools and Drugs ; Peptide Fragments - pharmacology ; Pipecolic Acids - pharmacology ; Plasma - drug effects ; Plasma - metabolism ; Platelet diseases and coagulopathies ; Porosity ; Protein Multimerization ; recombinant FVIII ; Recombinant Proteins - pharmacology ; thrombin inhibitor ; Thrombosis - metabolism ; Tissue Plasminogen Activator - metabolism
É parte de: Thrombosis and haemostasis, 2010-05, Vol.103 (5), p.1076-1084
Descrição: 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.
Editor: Stuttgart: Schattauer Verlag für Medizin und Naturwissenschaften
Idioma: Inglês

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

SHU HE ; BLOMBÄCK, Margareta ; BARK, Niklas ; JOHNSSON, Hans ; WALLEN, N. Hakan

Stuttgart: Schattauer Verlag für Medizin und Naturwissenschaften

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