Plasmatic tissue factor pathway inhibitor is a major determinant of clotting in factor VIII inhibited plasma or blood

Sabine Knappe; Monika E. Gorczyca; Bernd Jilma; Ulla Derhaschnig; Rudolf Hartmann; Michael Palige; Fritz Scheiflinger; Michael Dockal

doi:10.1160/TH12-07-0529

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost 2013; 109(03): 450-457
DOI: 10.1160/TH12-07-0529

Blood Coagulation, Fibrinolysis and Cellular Haemostasis

Schattauer GmbH

Plasmatic tissue factor pathway inhibitor is a major determinant of clotting in factor VIII inhibited plasma or blood

Authors

Sabine Knappe

⁴Baxter Innovations GmbH, Vienna, Austria
Monika E. Gorczyca^*

¹Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

²Department of Otolaryngology, Medical University of Vienna, Vienna, Austria
Bernd Jilma

¹Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria
Ulla Derhaschnig

¹Department of Clinical Pharmacology, Medical University of Vienna, Vienna, Austria

³Department of Emergency Medicine, Medical University of Vienna, Vienna, Austria
Rudolf Hartmann

⁴Baxter Innovations GmbH, Vienna, Austria
Michael Palige

⁴Baxter Innovations GmbH, Vienna, Austria
Fritz Scheiflinger

⁴Baxter Innovations GmbH, Vienna, Austria
Michael Dockal

⁴Baxter Innovations GmbH, Vienna, Austria

Abstract

Summary

Tissue factor pathway inhibitor (TFPI) is a major inhibitor of coagulation. We therefore hypothesised that high plasmatic TFPI levels are associated with impaired ex vivo clotting in a model of acquired haemophilia. Blood samples were collected in a prospective clinical study from 30 healthy volunteers. Coagulation in normal or factor VIII (FVIII)-inhibited human blood or plasma was measured by the calibrated automated thrombogram (CAT) and rotational thromboelastometry (ROTEM). Both methods are global haemostatic assays that provide insight into the whole coagulation process. Monoclonal mouse antibodies raised against either the C-terminus or the Kunitz domain 2 of TFPI were used to determine full-length (fl-) and total TFPI by an enzyme-immunoassay. Clotting times and parameters of thrombin generation correlated with TFPI levels. Subjects with low fl-TFPI levels had significantly shorter clotting times and a higher endogenous thrombin potential (ETP) compared to those with high fl-TFPI levels (p≤0.005 for all). An even stronger effect was seen in FVIII-inhibited blood/plasma: ROTEM clotting time was 26% shorter (p=0.01) and the ETP assessed by CAT was >2-fold higher in subjects with low fl-TFPI levels (p≤0.0001). Plasmatic TFPI is a major determinant of coagulation in global haemostatic tests particularly when FVIII is missing. Thus, inhibition of TFPI might be a promising novel treatment approach, especially in haemophilia patients with FVIII inhibitors.

Keywords

Tissue factor pathway inhibitor - TFPI - coagulation factor FVIII - calibrated automated thrombin generation assay (CAT) - rotational thromboelastometry (ROTEM) - haemophilia

Full Text

References

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