Pharmacokinetics and delayed experimental anti-thrombotic effect of two domain non-glycosylated tissue factor pathway inhibitor
(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.
(Less)
- author
- Holst, Jan LU ; Lindblad, Bengt LU ; Westerlund, Gertie ; Bregengaard, Claus ; Ezban, Mirella ; ØStergaard, Per B. ; Nordfang, Ole and Hedner, Ulla LU
- publishing date
- 1996-02-15
- 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
- external identifiers
-
- scopus:0029923549
- pmid:8907295
- 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
- 2024-01-14 18:02:18
@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}},
keywords = {{experimental thrombosis; LMWH; pharmacokinetics; TFPI}},
language = {{eng}},
month = {{02}},
number = {{4}},
pages = {{461--470}},
publisher = {{Elsevier}},
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}},
doi = {{10.1016/0049-3848(96)00018-7}},
volume = {{81}},
year = {{1996}},
}