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Title: Antidote strategies to reverse anticoagulation with TB-402, a long-acting partial inhibitor of factor VIII
Authors: Tangelder, M ×
Long, C
Emmerechts, J
Jacquemin, Marc
Peerlinck, Kathelijne
Vanassche, Thomas
Glazer, S
Giesen, P
Hoylaerts, Marc
Verhamme, Peter #
Issue Date: Jul-2012
Publisher: Blackwell Pub.
Series Title: Journal of Thrombosis and Haemostasis vol:10 issue:7 pages:1371-1378
Abstract: . Background: TB-402 is a partially inhibiting antibody of factor VIII that is under development as a long-acting anticoagulant. Patients and Methods: The reversibility of FVIII inhibition by TB-402 was evaluated in vitro after spiking with recombinant human FVIII (rhFVIII), human plasma-derived FVIII (hpdFVIII), recombinant activated human FVII (rhFVIIa), FVIII inhibitor bypassing activity (FEIBA), and prothrombin complex concentrate (PCC). Twelve subjects were randomized to placebo or 35 or 70 IU kg-1 rhFVIII 48 h after a single dose of 620 mu g kg-1 TB-402. TB-402 concentrations, FVIII activity (FVIII:C), activated partial thromboplastin time (APTT) and thrombin generation were measured over a period of 8 weeks. Results: In spiked samples, TB-402 inhibited FVIII:C by 30%, prolonged APTT by 4.5 s, and reduced the peak height in the thrombin generation assay to 56% +/- 13% of the control value. In the presence of 10 mu g mL-1 TB-402, rhFVIII restored FVIII:C and APTT to the values obtained in the absence of TB-402. The inhibitory effect of TB-402 on thrombin generation was entirely reversed by rhFVIII, hpdFVIII, rhFVIIa, FEIBA, and PCC. In men, the mean half-life (t1/2) of TB-402 was 14.2 days. TB-402 lowered the endogenous thrombin potential by 23% for 35 days. Infusion of 35 IU kg-1 rhFVIII had a marginal effect, whereas 70 IU kg-1 rhFVIII restored FVIII:C, reduced APTT back to baseline for 9 h, and restored thrombin generation for 3 h. Conclusions: TB-402 resulted in a stable long-term anticoagulant effect. rhFVIII and other procoagulants counteracted the effect of TB-402 temporarily, and may be effective antidotes for future clinical practice.
ISSN: 1538-7933
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular and Vascular Biology
× corresponding author
# (joint) last author

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