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Thromb Haemost 1996; 75(04): 585-589
DOI: 10.1055/s-0038-1650326
Original Article
Schattauer GmbH Stuttgart

Experimental Haemorrhagic Effect of Two-Domain Non-Glycosylated Tissue Factor Pathway Inhibitor Compared to Low Molecular Weight Heparin

Jan Holst
1   The Dept. of Surgery, Helsirrgborg Hospital, Helsingborg, Sweden
2   Dept. of Surgery and Experimental Research, Malmö University Hospital, Malmö, Sweden
,
Bengt Lindblad
2   Dept. of Surgery and Experimental Research, Malmö University Hospital, Malmö, Sweden
,
Stefan E Matthíasson
2   Dept. of Surgery and Experimental Research, Malmö University Hospital, Malmö, Sweden
,
Ulf Stjernquist
2   Dept. of Surgery and Experimental Research, Malmö University Hospital, Malmö, Sweden
,
Mirella Ezban
3   Novo Nordisk A/S, Gentofte, Denmark
,
Per B Østergaard
3   Novo Nordisk A/S, Gentofte, Denmark
,
Ulla Hedner
3   Novo Nordisk A/S, Gentofte, Denmark
› Author Affiliations
Further Information

Publication History

Received 07 July 1995

Accepted after resubmission 18 December 1995

Publication Date:
10 July 2018 (online)

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Summary

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 117QTFPIM61−161 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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