Structural requirements for tissue factor pathway inhibitor interactions with factor Xa and heparin

Wesselschmidt, Robin L.; Likert, Karen M.; Huang, Zhenhua; MacPhail, L; Broze, George J.

doi:10.1097/00001721-199304050-00001

Cited by 94 publications

(48 citation statements)

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“…on May 12, 2018. by guest www.bloodjournal.org From Analysis of this sequence, which codes for a protein named Desmolaris, indicated that it contains, similarly to TFPI, a basic carboxyl-terminal (C-terminal) that confers binding to heparin 34 and optimal inhibition of FXa. 35 In contrast, Desmolaris presents a natural deletion of the Kunitz-1 domain of TFPI that mediates interaction with FVIIa/TF.…”

Section: Discussionmentioning

confidence: 99%

Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

Mizurini

Assumpção

et al. 2013

Blood

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Section: Discussionmentioning

confidence: 99%

Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

Mizurini

Assumpção

et al. 2013

Blood

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“…Plausibly, heparin functions as an anchor that targets Alboserpin to endothelial cells, localizing it at the site of injury, where it remains bound instead of free in solution, resulting in higher effective concentration. In this context, tissue factor pathway inhibitor and vascular endothelial growth factor binding to heparin has also been demonstrated and sought to contribute to localization in endothelial cells and other glycosaminoglycan-bearing cells (48,49).…”

Section: Specifiticy Of Alboserpin-mentioning

confidence: 99%

Alboserpin, a Factor Xa Inhibitor from the Mosquito Vector of Yellow Fever, Binds Heparin and Membrane Phospholipids and Exhibits Antithrombotic Activity

Calvo

Mizurini

Sá-Nunes

et al. 2011

Journal of Biological Chemistry

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The molecular mechanism of factor Xa (FXa) inhibition by Alboserpin, the major salivary gland anticoagulant from the mosquito and yellow fever vector Aedes albopictus, has been characterized. cDNA of Alboserpin predicts a 45-kDa protein that belongs to the serpin family of protease inhibitors. Recombinant Alboserpin displays stoichiometric, competitive, reversible and tight binding to FXa (picomolar range). Binding is highly specific and is not detectable for FX, catalytic siteblocked FXa, thrombin, and 12 other enzymes. Alboserpin displays high affinity binding to heparin (K D ϳ 20 nM), but no change in FXa inhibition was observed in the presence of the cofactor, implying that bridging mechanisms did not take place. Notably, Alboserpin was also found to interact with phosphatidylcholine and phosphatidylethanolamine but not with phosphatidylserine. Further, annexin V (in the absence of Ca 2؉ ) or heparin outcompetes Alboserpin for binding to phospholipid vesicles, suggesting a common binding site. Consistent with its activity, Alboserpin blocks prothrombinase activity and increases both prothrombin time and activated partial thromboplastin time in vitro or ex vivo. Furthermore, Alboserpin prevents thrombus formation provoked by ferric chloride injury of the carotid artery and increases bleeding in a dose-dependent manner. Alboserpin emerges as an atypical serpin that targets FXa and displays unique phospholipid specificity. It conceivably uses heparin and phosphatidylcholine/phosphatidylethanolamine as anchors to increase protein localization and effective concentration at sites of injury, cell activation, or inflammation.

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“…23 The first Kunitz domain binds to and inhibits FVIIa, the second binds to and inhibits FXa, and the C-terminal tail was proposed to bind to heparin-like structures on the vessel wall. 24 Kunitz-3 contains a heparin binding site, 25 the function of which is unknown. However, in various truncated forms of TFPI, Kunitz-3 is involved in cross-disulfide bonding between TFPI and low-density lipoprotein.…”

Section: Tfpimentioning

confidence: 99%

Protein S as Cofactor for TFPI

Hackeng

Rosing

2009

ATVB

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Abstract-In the last decades evidence was obtained that protein S not only acts as cofactor of activated protein C (APC) in the downregulation of coagulation, but also expresses anticoagulant activity in the absence of APC. The search for the mechanism(s) underlying the APC-independent anticoagulant activity of protein S was hampered by the fact that protein S exhibited 2 seemingly identical anticoagulant activities in model systems and in plasma. Later it was shown that the anticoagulant activity of purified protein S in model systems was dependent on the concentration of phospholipid vesicles and was explained by low amounts of protein S multimers generated during purification that effectively inhibited phospholipid-dependent coagulation reactions via competition for phospholipid binding sites. Plasma does not contain multimers, and the anticoagulant activity of protein S in plasma was not affected by the phospholipid concentration but was dependent on the amount of tissue factor (TF) used for initiation of thrombin generation. This led to the discovery that protein S acts as cofactor of tissue factor pathway inhibitor (TFPI) which stimulates the inhibition of factor Xa by TFPI Ϸ10-fold. The current review describes the background of the TFPI-cofactor activity of protein S as well as the rationale for the observation that the TFPI/protein S system particularly inhibits the TF pathway at low procoagulant stimuli. . It is well known that protein S acts as a cofactor of activated protein C (APC) in the proteolytic inactivation of blood coagulation factors Va and VIIIa, thus providing a negative feedback on coagulation and making the APC/protein S pathway essential for normal hemostasis. [2][3][4][5] Homozygous deficiencies in either protein C or protein S result in severe neonatal procoagulant phenotypes, whereas heterozygous deficiencies are associated with a 10-fold increased risk of venous thrombosis. 6 -8 More recently it has been shown that protein S also effectively inhibits thrombin generation in plasma in the absence of APC. 9 This anticoagulant property of protein S was especially observed at low TF concentrations (Ϸ1 pmol/L) leading to the concept that protein S took part in regulating the initiation phase of coagulation and effectively counteracts ongoing procoagulant processes in the circulation. 10 Interestingly, protein S had no effect on thrombin generation when coagulation was initiated through the intrinsic route, regardless of the amount of trigger used. 5 Because of the dependence of the anticoagulant activity of protein S on the TF concentration, a new role of protein S was identified as a cofactor for TFPI in the inhibition of FXa. 11 In contrast to investigations in plasma, many studies were performed in model systems using purified protein S preparations that also led to reports about APC-independent anticoagulant properties of protein S. [12][13][14][15][16] Although the anticoagulant activities in plasma and in model systems containing purified proteins initially looked mechanistic...

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Structural requirements for tissue factor pathway inhibitor interactions with factor Xa and heparin

Cited by 94 publications

References 0 publications

Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

Desmolaris, a novel factor XIa anticoagulant from the salivary gland of the vampire bat (Desmodus rotundus) inhibits inflammation and thrombosis in vivo

Alboserpin, a Factor Xa Inhibitor from the Mosquito Vector of Yellow Fever, Binds Heparin and Membrane Phospholipids and Exhibits Antithrombotic Activity

Protein S as Cofactor for TFPI

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