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Does glycosylation influence the experimental antithrombotic effect of a two-domain tissue factor pathway inhibitor?

Holst, Jan LU ; Lindblad, Beugt LU ; Nordfang, Oie; Østergaard, Per B. and Hedner, Ulla LU (1996) In Pathophysiology of Haemostasis and Thrombosis 26(1). p.23-30
Abstract

We have earlier shown that both full-length and truncated glycosylated tissue factor pathway inhibitor (TFPI) lacking the third Kunitz domain and the c-terminal region has an antithrombotic effect comparable to low-molecular-weight heparin (LMWH) in an experimental venous thrombosis model. The aim of this study was to investigate whether a recombinant truncated non-glycosylated TFPI (117QTFPI1-161) had an antithrombotic effect similar to the glycosylated TFPI1-161 and LMWH. We also followed the coagulation parameters. The thrombi were induced in rabbit jugular veins with a combination of endothelium destruction and restricted blood flow. Group 1: placebo; group 2: LMWH 60 anti-Xa IU/kg, i.v.; groups 3 and 4:... (More)

We have earlier shown that both full-length and truncated glycosylated tissue factor pathway inhibitor (TFPI) lacking the third Kunitz domain and the c-terminal region has an antithrombotic effect comparable to low-molecular-weight heparin (LMWH) in an experimental venous thrombosis model. The aim of this study was to investigate whether a recombinant truncated non-glycosylated TFPI (117QTFPI1-161) had an antithrombotic effect similar to the glycosylated TFPI1-161 and LMWH. We also followed the coagulation parameters. The thrombi were induced in rabbit jugular veins with a combination of endothelium destruction and restricted blood flow. Group 1: placebo; group 2: LMWH 60 anti-Xa IU/kg, i.v.; groups 3 and 4: TFPI1-161 0.8 and 0.2 mg/kg, i.v. respectively; groups 5 and 6: 0.8 and 0.2 mg/kg 117QTFPI1-161, i.v. respectively, in a randomized double-dummy fashion. Twelve animals were included in the placebo group and 6 in each of the other groups. The frequency of thrombosis and also of occlusive thrombosis was reduced in all groups compared to placebo. The thrombus weight was reduced (0-9.9 mg) in all groups, significantly in groups 2, 4 and 5 (p = 0.004-0.02) compared to placebo (21.1 mg). In group 3, a borderline p value was achieved (0.06 likely a β-error). The two forms of TFPI1-161 given in the higher doses showed a significantly greater increase of anti-Xa activity, but with a shorter duration compared to LMWH (1.7-1.9 vs. 0.9 anti-Xa IU/ml). Activated partial thromboplastin time (aPTT)-analysis revealed that only LMWH (52 s) caused a significant transient elevation 2 min after injection. In the other groups, a temporary but insignificant elevation of aPTT (27-37 s) was seen. No detectable effect on anti-Xa activity and prothrombin time (PT) was seen in any TFPI group. The glycosylation of the second domain on TFPI does not substantially contribute to the antithrombotic effect of TFPI. Regardless of the glycosylation of TFPl1-161, it has a dose-dependent effect on anti-Xa, a small effect on the aPTT, but no effect on anti-Xa and PT. LMWH has a more pronounced and sustained impact on these parameters.

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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Experimental thrombosis, Glycosylation, Low-molecular-weight heparin, Tissue factor pathway inhibitor
in
Pathophysiology of Haemostasis and Thrombosis
volume
26
issue
1
pages
23 - 30
publisher
Karger
external identifiers
  • scopus:0030032907
ISSN
1424-8832
DOI
10.1159/000217184
language
English
LU publication?
yes
id
cf974821-4668-424c-9eb0-4a087572770f
date added to LUP
2018-04-05 15:56:43
date last changed
2018-11-21 21:39:07
@article{cf974821-4668-424c-9eb0-4a087572770f,
  abstract     = {<p>We have earlier shown that both full-length and truncated glycosylated tissue factor pathway inhibitor (TFPI) lacking the third Kunitz domain and the c-terminal region has an antithrombotic effect comparable to low-molecular-weight heparin (LMWH) in an experimental venous thrombosis model. The aim of this study was to investigate whether a recombinant truncated non-glycosylated TFPI (117QTFPI<sub>1-161</sub>) had an antithrombotic effect similar to the glycosylated TFPI<sub>1-161</sub> and LMWH. We also followed the coagulation parameters. The thrombi were induced in rabbit jugular veins with a combination of endothelium destruction and restricted blood flow. Group 1: placebo; group 2: LMWH 60 anti-Xa IU/kg, i.v.; groups 3 and 4: TFPI<sub>1-161</sub> 0.8 and 0.2 mg/kg, i.v. respectively; groups 5 and 6: 0.8 and 0.2 mg/kg 117QTFPI<sub>1-161</sub>, i.v. respectively, in a randomized double-dummy fashion. Twelve animals were included in the placebo group and 6 in each of the other groups. The frequency of thrombosis and also of occlusive thrombosis was reduced in all groups compared to placebo. The thrombus weight was reduced (0-9.9 mg) in all groups, significantly in groups 2, 4 and 5 (p = 0.004-0.02) compared to placebo (21.1 mg). In group 3, a borderline p value was achieved (0.06 likely a β-error). The two forms of TFPI<sub>1-161</sub> given in the higher doses showed a significantly greater increase of anti-Xa activity, but with a shorter duration compared to LMWH (1.7-1.9 vs. 0.9 anti-Xa IU/ml). Activated partial thromboplastin time (aPTT)-analysis revealed that only LMWH (52 s) caused a significant transient elevation 2 min after injection. In the other groups, a temporary but insignificant elevation of aPTT (27-37 s) was seen. No detectable effect on anti-Xa activity and prothrombin time (PT) was seen in any TFPI group. The glycosylation of the second domain on TFPI does not substantially contribute to the antithrombotic effect of TFPI. Regardless of the glycosylation of TFPl<sub>1-161</sub>, it has a dose-dependent effect on anti-Xa, a small effect on the aPTT, but no effect on anti-Xa and PT. LMWH has a more pronounced and sustained impact on these parameters.</p>},
  author       = {Holst, Jan and Lindblad, Beugt and Nordfang, Oie and Østergaard, Per B. and Hedner, Ulla},
  issn         = {1424-8832},
  keyword      = {Experimental thrombosis,Glycosylation,Low-molecular-weight heparin,Tissue factor pathway inhibitor},
  language     = {eng},
  month        = {01},
  number       = {1},
  pages        = {23--30},
  publisher    = {Karger},
  series       = {Pathophysiology of Haemostasis and Thrombosis},
  title        = {Does glycosylation influence the experimental antithrombotic effect of a two-domain tissue factor pathway inhibitor?},
  url          = {http://dx.doi.org/10.1159/000217184},
  volume       = {26},
  year         = {1996},
}