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

Holst, Jan LU ; Lindblad, Bengt LU ; Westerlund, Gertie; Bregengaard, Claus; Ezban, Mirella; ØStergaard, Per B.; Nordfang, Ole and Hedner, Ulla LU (1996) In Thrombosis Research 81(4). p.461-470
Abstract

Tissue Factor Pathway Inhibitor (TFPI) is a naturally occurring inhibitor of the TF-FVIIa 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 (117QTFPI1-161), was evaluated regarding pharmacokinetics and delayed antithrombotic potential in the rabbit. Pharmacokinetic study 117QTFPI1-161 vs glycosylated TFPI1-161. 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 117QTFPI1-161 (37 vs 10 min). Clearance of... (More)

Tissue Factor Pathway Inhibitor (TFPI) is a naturally occurring inhibitor of the TF-FVIIa 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 (117QTFPI1-161), was evaluated regarding pharmacokinetics and delayed antithrombotic potential in the rabbit. Pharmacokinetic study 117QTFPI1-161 vs glycosylated TFPI1-161. 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 117QTFPI1-161 (37 vs 10 min). Clearance of 117QTFPI1-161 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 + 117QTFPI1-161 0,25 mg/kg, 117QTFPI1-161 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 blood flow in the jugular veins. The thrombusweight was significantly reduced in LMWH and 117QTFPI1-161 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 117QTFPI1-161 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. 117QTFPI1-161 (1,0 and 4,0 mg) has an antithrombotic effect indistinguishable from LMWH even though given 60 min before the thrombus induction 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.

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author
publishing date
type
Contribution to journal
publication status
published
keywords
experimental thrombosis, LMWH, pharmacokinetics, TFPI
in
Thrombosis Research
volume
81
issue
4
pages
461 - 470
publisher
Elsevier Ltd
external identifiers
  • scopus:0029923549
ISSN
0049-3848
DOI
10.1016/0049-3848(96)00018-7
language
English
LU publication?
no
id
2500ec74-3f49-4aaa-8bab-855b97435a99
date added to LUP
2018-04-05 15:51:38
date last changed
2018-10-28 04:52:12
@article{2500ec74-3f49-4aaa-8bab-855b97435a99,
  abstract     = {<p>Tissue Factor Pathway Inhibitor (TFPI) is a naturally occurring inhibitor of the TF-FVIIa 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<sub>1-161</sub>), was evaluated regarding pharmacokinetics and delayed antithrombotic potential in the rabbit. Pharmacokinetic study 117QTFPI<sub>1-161</sub> vs glycosylated TFPI<sub>1-161</sub>. 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<sub>1-161</sub> (37 vs 10 min). Clearance of 117QTFPI<sub>1-161</sub> 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<sub>1-161</sub> 0,25 mg/kg, 117QTFPI<sub>1-161</sub> 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 blood flow in the jugular veins. The thrombusweight was significantly reduced in LMWH and 117QTFPI<sub>1-161</sub> 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<sub>1-161</sub> 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<sub>1-161</sub> (1,0 and 4,0 mg) has an antithrombotic effect indistinguishable from LMWH even though given 60 min before the thrombus induction 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.</p>},
  author       = {Holst, Jan and Lindblad, Bengt and Westerlund, Gertie and Bregengaard, Claus and Ezban, Mirella and ØStergaard, Per B. and Nordfang, Ole and Hedner, Ulla},
  issn         = {0049-3848},
  keyword      = {experimental thrombosis,LMWH,pharmacokinetics,TFPI},
  language     = {eng},
  month        = {02},
  number       = {4},
  pages        = {461--470},
  publisher    = {Elsevier Ltd},
  series       = {Thrombosis Research},
  title        = {Pharmacokinetics and delayed experimental anti-thrombotic effect of two domain non-glycosylated tissue factor pathway inhibitor},
  url          = {http://dx.doi.org/10.1016/0049-3848(96)00018-7},
  volume       = {81},
  year         = {1996},
}