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Experimental haemorrhagic effect of two-domain non-glycosylated tissue factor pathway inhibitor compared to low molecular weight heparin

Holst, Jan LU ; Lindblad, Bengt LU ; Matthíasson, Stefan E.; Stjernquist, Ulf; Ezban, Mirella; Østergaard, Per B. and Hedner, Ulla LU (1996) In Thrombosis and Haemostasis 75(4). p.585-589
Abstract

The glycosylated multivalent three-domain Kunitz inhibitor TFPI is a natural inhibitor of tissue factor-FVIIa complex in the presence of FXa. TFPI has an experimental antithrombotic capacity indistinguishable from LMWH in a prophylactic dose, regardless of glycosylation and of the third domain. An inherited equilibrium between antithrombosis and haemorrhage exists. The aim of the study was to evaluate whether a two-domain non-glycosylated TFPI (117QTFPI1-161) has a bleeding potential in a rat gastric mucosa model. Groups; placebo, LMWH (tinzaparin) 60 and 250 anti-Xa IU/kg and 117QTFPI1-161 1.0 and 10.0 mg/kg, given i.v. (bolus injection), randomised double dummy design. All actively treated groups significantly... (More)

The glycosylated multivalent three-domain Kunitz inhibitor TFPI is a natural inhibitor of tissue factor-FVIIa complex in the presence of FXa. TFPI has an experimental antithrombotic capacity indistinguishable from LMWH in a prophylactic dose, regardless of glycosylation and of the third domain. An inherited equilibrium between antithrombosis and haemorrhage exists. The aim of the study was to evaluate whether a two-domain non-glycosylated TFPI (117QTFPI1-161) has a bleeding potential in a rat gastric mucosa model. Groups; placebo, LMWH (tinzaparin) 60 and 250 anti-Xa IU/kg and 117QTFPI1-161 1.0 and 10.0 mg/kg, given i.v. (bolus injection), randomised double dummy design. All actively treated groups significantly prolonged both the bleeding volume (493-984 μl) and the bleeding time (10-20 min) compared to placebo (41 μl, 2 min). It was not possible to distinguish a difference between the lower dose of LMWH and 117QTFPI1-161 in either parameter (p = 0.23-0.71). The two doses of 117QTFPI1-161 caused elevation of plasma-TFPI, 18 and 150 times baseline value. Both LMWH doses (0.6-3.2 anti-Xa IU/ml) and both 117QTFPI1-161 doses (0.2-2.7 anti-Xa IU/ml), caused significant effect in the anti-Xa assay, however 117QTFPI1-161 significantly less. Only the largest dose of 117QTFPI1-161 caused significant prolongation in the APTT assay (34 s). Both doses of LMWH caused significant prolongation (60-300 s). LMWH was the only substance to prolong the dilute-PT assay. Non-glycosylated two-domain 1.0 mg/kg TFPI, yielding supra physiological plasma concentration, has an experimental haemorrhagic potential indistinguishable from LMWH in a prophylactic dose. The effect mediated by this type of TFPI could primarily be due to an inhibition of FXa.

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author
publishing date
type
Contribution to journal
publication status
published
in
Thrombosis and Haemostasis
volume
75
issue
4
pages
585 - 589
publisher
F K Schattauer Verlag Gmbh
external identifiers
  • scopus:0029997618
ISSN
0340-6245
language
English
LU publication?
no
id
d1688f7d-83de-463f-a618-f95f068afde6
date added to LUP
2018-03-23 16:06:32
date last changed
2018-05-29 09:43:28
@article{d1688f7d-83de-463f-a618-f95f068afde6,
  abstract     = {<p>The glycosylated multivalent three-domain Kunitz inhibitor TFPI is a natural inhibitor of tissue factor-FVIIa complex in the presence of FXa. TFPI has an experimental antithrombotic capacity indistinguishable from LMWH in a prophylactic dose, regardless of glycosylation and of the third domain. An inherited equilibrium between antithrombosis and haemorrhage exists. The aim of the study was to evaluate whether a two-domain non-glycosylated TFPI (117QTFPI<sub>1-161</sub>) has a bleeding potential in a rat gastric mucosa model. Groups; placebo, LMWH (tinzaparin) 60 and 250 anti-Xa IU/kg and 117QTFPI<sub>1-161</sub> 1.0 and 10.0 mg/kg, given i.v. (bolus injection), randomised double dummy design. All actively treated groups significantly prolonged both the bleeding volume (493-984 μl) and the bleeding time (10-20 min) compared to placebo (41 μl, 2 min). It was not possible to distinguish a difference between the lower dose of LMWH and 117QTFPI<sub>1-161</sub> in either parameter (p = 0.23-0.71). The two doses of 117QTFPI<sub>1-161</sub> caused elevation of plasma-TFPI, 18 and 150 times baseline value. Both LMWH doses (0.6-3.2 anti-Xa IU/ml) and both 117QTFPI<sub>1-161</sub> doses (0.2-2.7 anti-Xa IU/ml), caused significant effect in the anti-Xa assay, however 117QTFPI<sub>1-161</sub> significantly less. Only the largest dose of 117QTFPI<sub>1-161</sub> caused significant prolongation in the APTT assay (34 s). Both doses of LMWH caused significant prolongation (60-300 s). LMWH was the only substance to prolong the dilute-PT assay. Non-glycosylated two-domain 1.0 mg/kg TFPI, yielding supra physiological plasma concentration, has an experimental haemorrhagic potential indistinguishable from LMWH in a prophylactic dose. The effect mediated by this type of TFPI could primarily be due to an inhibition of FXa.</p>},
  author       = {Holst, Jan and Lindblad, Bengt and Matthíasson, Stefan E. and Stjernquist, Ulf and Ezban, Mirella and Østergaard, Per B. and Hedner, Ulla},
  issn         = {0340-6245},
  language     = {eng},
  number       = {4},
  pages        = {585--589},
  publisher    = {F K Schattauer Verlag Gmbh},
  series       = {Thrombosis and Haemostasis},
  title        = {Experimental haemorrhagic effect of two-domain non-glycosylated tissue factor pathway inhibitor compared to low molecular weight heparin},
  volume       = {75},
  year         = {1996},
}