The association between protein S levels and anticoagulant activity of tissue factor pathway inhibitor type 1

Dahm, Anders Erik Astrup; Sandset, Per Morten; Rosendaal, Frits R.

doi:10.1111/j.1538-7836.2007.02859.x

Cited by 24 publications

(25 citation statements)

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“…FV levels were still an important determinant of both TFPI parameters. We have previously shown that free and total protein S are associated with TFPI levels, but without influencing the risk for VT [9]. Thus, it was not surprising that they were the strongest determinants of TFPI free antigen.…”

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confidence: 97%

Interaction between tissue factor pathway inhibitor and factor V levels on the risk of venous thrombosis

Dahm

Bezemer

Sandset

et al. 2010

Journal of Thrombosis and Haemostasis

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To cite this article: Dahm AEA, Bezemer ID, Sandset PM, Rosendaal FR. Interaction between tissue factor pathway inhibitor and factor V levels on the risk of venous thrombosis. J Thromb Haemost 2010; 8: 1130-2.Tissue factor pathway inhibitor 1 (TFPI) inhibits blood coagulation by forming a quaternary complex with activated coagulation factor X (FXa), activated factor (F) VII and tissue factor [1]. In plasma, 80% of TFPI is truncated and bound to lipoproteins, whereas 20% is free full-length TFPI [2]. Low levels of both truncated and full-length TFPI are weak risk factors for venous thrombosis (VT) [3]. Inherited deficiencies of TFPI have not been reported.Factor V (FV) is an important, rate-limiting coagulation factor. Together with FXa, Ca 2+ and phospholipids, activated FV forms the prothrombinase complex, which converts prothrombin to thrombin. High or low plasma levels of FV appear not to influence the risk of VT [4]. Familial deficiencies of FV are rare and follow an autosomal recessive trait. Individuals with homozygous FV-deficiency have a hemophilic phenotype, but bleeding symptoms vary between patients and there is no clear relationship between FV levels and symptoms [5].Recently, Duckers et al.[6] demonstrated a relationship between FV and TFPI. They showed that subjects deficient in FV had low levels of TFPI, which, when adjusted for FV levels, resulted in an activated protein C (APC) resistance that possibly protected against bleeding. They found that levels of FV and TFPI in healthy and FV-deficient subjects were associated, and that male patients deficient in FVIII had lower TFPI levels than healthy male controls.We have previously reported on the association between TFPI and FV in a study of low TFPI as a risk factor for VT [3]. At that time, there were no reports suggesting a relationship between TFPI and FV, and we interpreted FV as a weak determinant of TFPI levels, in line with the other coagulation factors studied. Consequently, FV levels were not considered when we estimated the TFPI-related risk for VT. As Duckers et al.[6] now have suggested a relationship between FV and TFPI, we wanted to study this association more thoroughly, as well as the relation between TFPI and other coagulation factors, including FVIII. Furthermore, we investigated the potential interaction between FV and TFPI levels related to the risk of thrombosis, in analogy to the influence on the risk for bleeding suggested by Duckers et al.[6].We analyzed data from The Leiden Thrombophilia Study, which is a case-control study of 474 cases with VT and 474 healthy controls [7]. For the current report, data from 425 controls (171 male) were available to study the association between TFPI levels and other coagulation factors. For the calculations of the risk of VT, oral contraceptive users at the time of blood sampling were excluded [3], leaving 426 cases and 397 controls. The study protocol was approved by the Leiden University Medical Center Ethics Committee. All participants gave written informed consent according to the Decl...

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Interaction between tissue factor pathway inhibitor and factor V levels on the risk of venous thrombosis

Dahm

Bezemer

Sandset

et al. 2010

Journal of Thrombosis and Haemostasis

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“…However, to our knowledge, hereditary deficiencies of TFPI have never been described in humans, but plasma TFPI levels show large inter-individual variations. Although the TFPI in plasma represents only a fraction of all TFPI and its physiologic significance remains uncertain, several studies have shown that low levels of plasma TFPI (particularly free TFPI) are associated with a approximately 2-fold increased risk of venous thromboembolism [3,[28][29][30].Interestingly, it has been recently reported that there is covariation of protein S and TFPI in normal individuals [31], and that plasma levels of full-length TFPI are low in protein S-deficient patients (Castoldi, Simioni, Tormene, Rosing and Hackeng, submitted). As TFPI and protein S act in close coordination to down-regulate thrombin generation in plasma both in the presence and absence of APC, combined low levels of both proteins may synergize in causing thrombosis.…”

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Regulation of TFPI function by protein S

Hackeng

Maurissen

Castoldi

et al. 2009

Journal of Thrombosis and Haemostasis

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Summary. Protein S is an anticoagulant cofactor of full-length tissue factor pathway inhibitor (TFPI) that facilitates optimal factor Xa-inhibition and efficient down-regulation of thrombin generation in plasma. Protein S and TFPI are constitutively active in plasma and therefore provide an effective anticoagulant barrier against unwanted procoagulant activity in the circulation. In this review, we describe the current status on how TFPI-activity depends on protein S, and show that TFPI and protein S are major regulators of thrombin generation both in the absence and presence of activated protein C (APC). As there is covariation of plasma TFPI and protein S levels both in health and in disease, these findings suggest that the risk of venous thrombosis associated with protein S deficiency states might be in part explained by the accompanying low plasma TFPI levels.Keywords: APC, protein S, TFPI, thrombosis. TFPIThe natural anticoagulant tissue factor pathway inhibitor (TFPI) regulates the initiation of coagulation by inhibiting both factor Xa (FXa) and the phospholipid-bound complex of tissue factor and factor VIIa (TF-FVIIa) [1,2]. TFPI is a Kunitz-type protease inhibitor comprising an acidic N-terminus, 3 Kunitz domains and a basic C-terminus [2]. TFPI is synthesized by endothelial cells and about 80% of the same associates with the vessel wall ( Fig. 1), whereas the remainder circulates in plasma at a concentration of approximately 2.5 nM [3,4]. The majority of TFPI in plasma (70-80%) is truncated and bound to low-density lipoproteins through disulfide bonds with . Only 10% of plasma TFPI (i.e. about 2% of total TFPI) is considered to be free full-length TFPI (Fig. 1). As a result of its intact positively charged C-terminal tail that interacts with anionic membrane surfaces, full-length TFPI is a more effective inhibitor than truncated TFPI [6,7]. Protein SProtein S is a vitamin K-dependent plasma protein that is mainly synthesized in hepatocytes and endothelial cells and circulates in plasma at a concentration of 350 nM [8]. More than half of the total protein S exists in a high-affinity complex (Kd approximately 0.1 nM) with C4b-binding protein (C4BP) and the molar excess of total protein S over C4BP circulates free [9]. Protein S, which lacks enzymatic activity, acts as a cofactor for activated protein C (APC) in the proteolytic inactivation of coagulation factors (F) Va and VIIIa [10] However, protein S was also shown to effectively reduce thrombin generation in plasma triggered at low TF concentrations (approximately 1 pM) in the absence of APC [14]. As no APC-independent anticoagulant activity of protein S was observed when coagulation was triggered via the intrinsic pathway, it was concluded that protein S participated in the regulation of the extrinsic pathway. These observations led us to discover that protein S is a cofactor for TFPI in the inhibition of FXa [15]. The in vitro-generated protein S multimers [16,17] are not involved in this anticoagulant activity of protein S. TFPI-protein S anticoagul...

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“…FXa inhibition is further enhanced by the binding of K3 to protein S [29], an interaction that requires Arg199 and Glu226 of K3 [30,31 ▪ ]. Additionally, plasma concentrations of these two proteins correlate in healthy individuals and fall in tandem in individuals treated with oral contraceptives [32,33 ▪ ,34]. TFPIα–protein S anticoagulant activity is observed in plasma clotting assays initiated with low TF (1 pmol/l) concentrations, but not at higher (14 pmol/l) concentrations [35,36].…”

Section: Tissue Factor Pathway Inhibitor α and Tissue Factor Pathway mentioning

confidence: 99%

Cellular expression and biological activities of alternatively spliced forms of tissue factor pathway inhibitor

Maroney

Hansen²,

Mast³

2013

Current Opinion in Hematology

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Purpose of review-Tissue factor pathway inhibitor (TFPI) is an anticoagulant protein that inhibits tissue factor-factor VIIa (TF-fVIIa) and factor Xa (fXa). Recent studies revealed distinct cellular expression patterns for TFPI and TFPI and spurred additional experiments to define unique functions for these alternatively spliced TFPI isoforms.Recent findings-TFPI is produced by endothelial cells, localizes to an intracellular granule, and is released following cellular stimulation with thrombin or heparin. TFPI also is produced by megakaryocytes and released from activated platelets. Platelet TFPI limits clot growth following vessel injury and alters bleeding in hemophilia, suggesting that its primary physiological role is modulation of clot development. TFPI is made by endothelial cells, localizes to the endothelium surface, and is not in platelets. TFPI is an effective inhibitor of TF-mediated cellular migration and may act to dampen the adverse effects of intravascular TF expressed during inflammation.Summary-Knowledge of TFPI isoform expression and activity provides new insights into the biochemical regulation of TF-mediated thrombotic and inflammatory disease. Recent findings have therapeutic implications for use of recombinant TFPI to treat severe sepsis in communityacquired pneumonia or to achieve improved engraftment of hematopoietic stem cells, and for development of TFPI-blocking pharmaceuticals to treat hemophilia.

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The association between protein S levels and anticoagulant activity of tissue factor pathway inhibitor type 1

Cited by 24 publications

References 10 publications

Interaction between tissue factor pathway inhibitor and factor V levels on the risk of venous thrombosis

Interaction between tissue factor pathway inhibitor and factor V levels on the risk of venous thrombosis

Regulation of TFPI function by protein S

Cellular expression and biological activities of alternatively spliced forms of tissue factor pathway inhibitor

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