Tissue factor pathway inhibitor anticoagulant activity: risk for venous thrombosis and effect of hormonal state

SummaryTissue factor pathway inhibitor (TFPI) is a feed back inhibitor of the initial activation of the extrinsic pathway of coagulation. In humans, injection of heparin results in a 2-6 fold increase in plasma TFPI and recent studies suggest that TFPI may be important for the anticoagulant activity of heparin. Full length (FL) TFPI, but not recombinant two-domain (2D) TFPI, has a poly cationic C-terminus showing very strong heparin binding. Therefore, we have investigated if heparin affects the pharmacokinetics of TFPI with and without this C-terminus.FL-TFPI (608 U/kg) and 2D-TFPI (337 U/kg) were injected intravenously in rabbits with and without simultaneous intravenous injections of low molecular weight heparin (450 anti-XaU/kg).Heparin decreased the volume of distribution and the clearance of FL-TFPI by a factor 10-15, whereas the pharmacokinetics of 2D-TFPI were unaffected by heparin. When heparin was administered 2 h following TFPI the recovery of FL-TFPI was similar to that found in the group receiving the two compounds simultaneously, suggesting that the releasable pool of FL-TFPI is removed very slowly in the absence of circulating heparin.

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The Significance of TFPI in Clotting Assays – Gomparison and Combination with other Anticoagulants

Thrombosis and Haemostasis ◽

10.1055/s-0038-1649603 ◽

1993 ◽

Vol 70 (03) ◽

pp. 448-453 ◽

Cited By ~ 12

Author(s):

Ole Nordfang ◽

Hanne I Kristensen ◽

Sanne Valentin ◽

Per Østergaard ◽

Johnny Wadt

Keyword(s):

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Antithrombin Iii ◽

Anticoagulant Activity ◽

Assay System ◽

Thrombin Inhibitor ◽

Clotting Time ◽

Normal Plasma ◽

Tissue Factor Pathway ◽

Plasma Heparin

SummaryThe anticoagulant activities of Tissue Factor Pathway Inhibitor (TFPI), heparin and hirudin were compared in intrinsic (APTT) and extrinsic (PT) activated clotting assays. In contrast to the thrombin inhibitor hirudin, heparin was 10 fold more potent in the APTT assay than in the PT assay, indicating that inhibition of intrinsic activation is important for the anticoagulant activity of heparin as measured in an APTT assay. TFPI was most potent in the PT assay and the effect of TFPI was most pronounced in the presence of other anticoagulants (heparin and hirudin). The activities of the two natural anticoagulants antithrombin III (ATIII) and TFPI were compared in a PT assay with very dilute tissue factor. In this assay system TFPI in normal plasma affected the clotting time more than ATIII in the plasma. However, when heparin was added ATIII was the major anticoagulant, but profound Prolongation of the clotting time was only seen when TFPI was also added. In an ATIII deficient plasma heparin did not augment the effect of TFPI, showing that the increased effect of TFPI in the presence of heparin is dependent on the anticoagulant activity of ATIII/heparin. The effect of TFPI at prolonged clotting times was also illustrated by the significant effect of blocking TFPI in the plasma from warfarin-treated patients. Thus TFPI is a major anticoagulant in normal plasma and the effect of TFPI is especially seen at prolonged clotting times.

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The 536C→T Transition in the Human Tissue Factor Pathway Inhibitor (TFPI) Gene Is Statistically Associated with a Higher Risk for Venous Thrombosis

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614619 ◽

1999 ◽

Vol 82 (07) ◽

pp. 1-5 ◽

Cited By ~ 14

Author(s):

Michael Schmidt ◽

Christian Götting ◽

Britt Schwenz ◽

Stefan Lange ◽

Gert Müller-Berghaus ◽

...

Keyword(s):

Venous Thrombosis ◽

Tissue Factor ◽

Tissue Factor Pathway Inhibitor ◽

Blood Donors ◽

Amino Acid Position ◽

Immunological Methods ◽

Venous Thromboembolic ◽

Coagulation Inhibitors ◽

Tissue Factor Pathway

SummaryTissue factor pathway inhibitor (TFPI) is an important regulator in the extrinsic blood coagulation pathway. Although the regulatory biochemical role of TFPI is evident, the clinical significance of this proteinase inhibitor remains to be elucidated. The definition of a clinical TFPI deficiency seems to be more complex than that of other coagulation inhibitors because the activity and concentration of circulating TFPI can not be considered a true measure of in vivo levels. Its determination in plasma samples by immunological methods or functional assays has been shown to be inadequate in the detection of a clinical deficiency.Therefore, we screened genomic DNA samples of blood donors and thrombotic patients for alterations in the TFPI gene to assess the influence of a modified TFPI in venous thromboembolic diseases. We detected a single nucleotide substitution in exon 7 (536C→T) leading to a proline to leucine exchange at amino acid position 151 of the protein ([P151L]TFPI) and found the prevalence of heterozygous carriers in German unrelated blood donors to be 0.2% (n = 5120).Four unrelated persons out of 14 probands carrying the genetic variation could be linked to venous thrombosis. For calculation of a potential risk for venous thrombosis for carriers of the mutation we investigated healthy blood donors about thrombotic events. 7 out of 308 blood donors were found to have a history of venous thrombosis, one of them carried the TFPI mutation. Statistical calculation showed a significant relative risk for venous thrombosis for individuals with the trait (odds ratio, 9.3; confidence interval, 1.8-48.6; p <0.01).

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Role of tissue factor pathway inhibitor in post surgical deep venous thrombosis (DVT) prophylaxis in patients treated with low molecular weight heparin

Thrombosis Research ◽

10.1016/0049-3848(94)90035-3 ◽

1994 ◽

Vol 74 (1) ◽

pp. 53-64 ◽

Cited By ~ 18

Author(s):

Richard Kijowski ◽

Debra Hoppensteadt ◽

Jeanine Walenga ◽

Lars Borris ◽

Michael Rud Lassen ◽

...

Keyword(s):

Molecular Weight ◽

Venous Thrombosis ◽

Deep Venous Thrombosis ◽

Tissue Factor ◽

Low Molecular Weight Heparin ◽

Tissue Factor Pathway Inhibitor ◽

Low Molecular Weight ◽

Dvt Prophylaxis ◽

Tissue Factor Pathway

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Abstract 43: Prothrombinase Assembled with Factor V Leiden is Resistant to Inhibition by Tissue Factor Pathway Inhibitor α Lowering the Procoagulant Threshold for Initiation of Coagulation

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvb.36.suppl_1.43 ◽

2016 ◽

Vol 36 (suppl_1) ◽

Author(s):

Jeremy P Wood ◽

Lisa M Baumann Kreuziger ◽

Susan A Maroney ◽

Rodney M Camire ◽

Alan E Mast

Keyword(s):

Tissue Factor ◽

Thrombin Generation ◽

Tissue Factor Pathway Inhibitor ◽

Platelet Rich Plasma ◽

Anticoagulant Activity ◽

Factor V Leiden ◽

Factor Xa ◽

Factor V ◽

Activation Threshold ◽

Tissue Factor Pathway

Factor V (FV) assembles with factor Xa (FXa) into prothrombinase, the enzymatic complex that converts prothrombin to thrombin. Tissue factor pathway inhibitor α (TFPIα) inhibits prothrombinase by high affinity interactions with FXa-activated FV and the FXa active site, thereby blocking the initiation of coagulation. FV Leiden (FVL) is strongly linked to venous thrombosis through its resistance to degradation by activated protein C (aPC), which enhances the propagation of coagulation. FVL combined with a 50% reduction in TFPI causes severe thrombosis and perinatal lethality in mice, suggesting that FVL also promotes the initiation of coagulation. To examine this possibility, thrombin generation assays initiated with limiting FXa were performed with control or FVL plasma and platelet-rich plasma (PRP). The activation threshold for thrombin generation was 10 to 20 pM FXa in 10 control plasmas, but was 5 pM in 4 of 10 homozygous FVL plasmas. FVL PRP had a similar decrease in the activation threshold. The differences in activation threshold were totally normalized by an anti-TFPI antibody, while exogenous TFPIα and a FV-binding peptide that mimics TFPIα had reduced anticoagulant activity in FVL plasma, revealing that the procoagulant effects of FVL in these assays rely on TFPIα. Next, FVL plasmas were studied in fibrin clot formation assays, as they are sensitive to small amounts of thrombin. In reactions activated with 0.5 pM FXa, 1 of 8 control plasmas, compared to 7 of 8 homozygous FVL plasmas, clotted within 60 minutes, with differences again normalized by the anti-TFPI antibody. In prothrombinase activity assays using purified proteins, TFPIα was a 1.7-fold weaker inhibitor of prothrombinase assembled with FVL compared to FV. Thus, in addition to its aPC-mediated effect on the propagation of coagulation, FVL is resistant to TFPIα inhibition, exerting a procoagulant effect on coagulation initiation. This is evident in responses to small stimuli, where TFPIα blocks clotting in plasmas with FV but not FVL. The TFPIα-mediated modulation of the procoagulant threshold may explain the severe perinatal thrombosis in FVL mice with decreased TFPI and be clinically relevant in the clotting associated with oral contraceptives, which cause acquired TFPI deficiency.

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