Pharmacokinetics and delayed experimental antithrombotic effect of two domain non-glycosylated tissue factor pathway inhibitor

Autor: Mirella Ezban, Gertie Westerlund, Bengt Lindblad, Jan Holst, Ulla Hedner, P. Østergaard, Ole Nordfang, Claus Bregengaard
Rok vydání: 1996
Předmět:
Zdroj: Thrombosis Research. 81:461-470
ISSN: 0049-3848
Popis: Tissue Factor Pathway Inhibitor (TFPI) is a naturally occurring inhibitor of the TFFVIIa induced coagulation in the presence of FXa. Recombinant two domain TFPI, where Asn 117 on the FXa-inhibitory domain was exchanged to a Gln yielding non-glycosylated TFPI (117QTFPI 1–161 ), was evaluated regarding pharmacokinetics and delayed antithrombotic potential in the rabbit. Pharmacokinetic study; 117QTFPI 1–161 vs glycosylated TFPI 1–161 . Three rabbits/group were used and received 1,0 mg/kg a bolus iv injection. Plasma-TFPI was measured for three hours. The α-phase half-life was similar, the β-phase half-life was close to four times longer for 117QTFPI 1–161 (37 vs 10 min). Clearance of 117QTFPI 1–161 was nearly two times lower (45 vs 21 ml/kg/min). Delayed anti-thrombotic study; 10 rabbits/group were used. 5 Groups; placebo+placebo, placebo+LMWH 60 anti-Xa IU/kg, placebo+117QTFPI 1–161 0,25 mg/kg, 117QTFPI 1–161 1,0 and 4,0 mg/kg+placebo. First injection 60 min prior to the second one, which coincided with the thrombus induction. The experimental thrombosis used combines a chemical destruction of the endothelium with a partial restriction of the bloodflow in the jugular veins. The thrombusweight was significantly reduced in LMWH and 117QTFPI 1–161 1,0 and 4,0 mg/kg groups (0,6–2,6 vs 11,8 mg). Frequency of occlusive thrombosis was significantly reduced in the LMWH and 117QTFPI 1–161 4,0 mg groups. All groups significantly effected the aXa-assay, the LMWH-group the most (0,85 IU/ml). LMWH was the only substance to prolong the dilute-PT-assay at the different timepoints. Absence of glycosylation increases the β-phase half-life and decreases clearance of two domain TFPI. 117QTFPI 1–161 (1,0 and 4,0 mg) has an antithrombotic effect indistinguishable from LMWH even though given 60 min before the thrombusinduction but with a considerable less effect on anti-Xa, APTT and no effect on dilute-PT. Glycosylation of TFPI influences the pharmacokinetics but not the antithrombotic capacity in this experimental setting.
Databáze: OpenAIRE
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