Improvement of spatial fibrin formation by the anti‐TFPI aptamer BAX499: changing clot size by targeting extrinsic pathway initiation
| Autor: | Leonid A. Parunov, Kathleen E. McGinness, Mikhail A. Panteleev, Natalia P. Soshitova, Fazoil I. Ataullakhanov, Konstantin G. Kopylov, James C. Gilbert, Robert G. Schaub, Maria A. Kumskova, Anna N. Balandina, Olga A. Fadeeva |
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| Rok vydání: | 2011 |
| Předmět: |
Male
medicine.medical_specialty Lipoproteins Stimulation Factor VIIa In Vitro Techniques Hemophilia A Models Biological Fibrin law.invention Tissue factor Tissue factor pathway inhibitor law medicine Humans Computer Simulation Blood Coagulation Hemostasis Microscopy Video biology Chemistry Antagonist Hematology Aptamers Nucleotide Recombinant Proteins Surgery Coagulation biology.protein Recombinant DNA Biophysics |
| Zdroj: | Journal of Thrombosis and Haemostasis. 9:1825-1834 |
| ISSN: | 1538-7836 |
| Popis: | Summary. Background: Tissue factor pathway inhibitor (TFPI) is a major regulator of clotting initiation and a promising target for pro- and anticoagulation therapy. The aptamer BAX499 (formerly ARC19499) is a high-affinity specific TFPI antagonist designed to improve hemostasis. However, it is not clear how stimulation of coagulation onset by inactivating TFPI will affect spatial and temporal clot propagation. Objective: To examine the BAX499 effect on clotting in a spatial, reaction-diffusion experimental system in comparison with that of recombinant activated factor VII (rVIIa). Methods: Clotting in plasma activated by immobilized tissue factor (TF) was monitored by videomicroscopy. Results: BAX499 dose-dependently improved coagulation in normal and hemophilia A plasma activated with TF at 2 pmole m−2 by shortening lag time and increasing clot size by up to ∼2-fold. The effect was TFPI specific as confirmed by experiments in TFPI-depleted plasma with or without TFPI supplementation. Clotting improvement was half-maximal at 0.7 nm of BAX499 and reached a plateau at 10 nm, remaining there at concentrations up to 1000 nm. The BAX499 effect decreased with TF surface density increase. RVIIa improved clotting in hemophilia A plasma activated with TF at 2 or 20 pmole m−2, both by shortening lag time and increasing spatial velocity of clot propagation; its effects were strongly concentration dependent. Conclusions: BAX499 significantly improves spatial coagulation by inhibiting TFPI in a spatially localized manner that is different to that observed with rVIIa. |
| Databáze: | OpenAIRE |
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