Factor Xa Cleavage of Tissue Factor Pathway Inhibitor Is Associated with Loss of Anticoagulant Activity

Salemink, Irene; Franssen, Jo; Willems, George M.; Hemker, H. Cœnraad; Li, Anguo; Wun, Tze-Chein; Lindhout, Théo

doi:10.1055/s-0037-1615187

Cited by 27 publications

(23 citation statements)

References 39 publications

(46 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…A previous study has shown that factor Xa can cleave the Lys86-Thr87 peptide bond between the K1 and K2 domains in recombinant TFPI. 33 Cleavage after Lys86 leads to the release of an N-terminal peptide with a calculated molecular mass of 10.08 kDa from mature TFPI, closely matching our observed size difference. This finding strongly suggests that the procoagulant effect of APC is mediated by cleavage of the TFPI Lys86-Thr87 peptide bond.…”

Section: Discussionsupporting

confidence: 81%

Activated protein C up-regulates procoagulant tissue factor activity on endothelial cells by shedding the TFPI Kunitz 1 domain

Schuepbach

Velez

Riewald

2011

Blood

View full text Add to dashboard Cite

Section: Discussionsupporting

confidence: 81%

Activated protein C up-regulates procoagulant tissue factor activity on endothelial cells by shedding the TFPI Kunitz 1 domain

Schuepbach

Velez

Riewald

2011

Blood

View full text Add to dashboard Cite

“…These include thrombin, plasmin, neutrophil elastase, and certain matrix metalloproteinases. 73,74 FXa, a natural target for TFPI, will also proteolyse TFPI after the K3 P1 residue (Arg199), but only when in molar excess. Although the cleavage of TFPI in vivo has not been well characterized, the plasmin-dependent reduction of both plasma and monocyte cell surface TFPI has been demonstrated in patients after thrombolytic therapy.…”

Section: Plasma Tfpimentioning

confidence: 99%

The Haemostatic Role of Tissue Factor Pathway Inhibitor

Crawley

Lane

2008

ATVB

133

112

View full text Add to dashboard Cite

Abstract-Under normal conditions the blood circulates freely within the confines of the vascular system, carrying oxygen, nutrients, and hormonal information around the body and removing metabolic waste. If blood gains access to extravascular sites, or the vasculature becomes pathologically challenged, hemostasis may be activated. This process is finely regulated by positive and negative feedback loops that modulate fibrin clot formation. Blood coagulation revolves around the activation and assembly of the components of the prothrombinase complex, which converts the inactive zymogen, prothrombin, into its active form, thrombin. This serine protease catalyzes the conversion of fibrinogen to fibrin, the structural scaffold that stabilizes platelet aggregates at sites of vascular injury. The extent of the hemostatic response is controlled by the action of inhibitory pathways, which ensure that thrombin activity and the spread of the hemostatic plug is limited to the site of vessel damage. This review article focuses on the major physiological regulator of tissue factor-induced coagulation, tissue factor pathway inhibitor, its expression, anticoagulant function, and its role in normal hemostasis.

show abstract

“…In addition to a full-length TFPI, it has been shown that truncated forms lacking most of their C-terminal domains are present in plasma and that they exhibit reduced affinity for vascular wall proteoglycans. In vitro experiments indicate that TFPI can be cleaved into partially degraded forms by various proteases, such as thrombin, 8 plasmin, 9 factor Xa, 10 and cell-derived matrix metalloproteinases, 11 as summarized in Figure 3. It remains to be established how the truncated forms of TFPI are generated in vivo by these proteases and by other proteases under physiological and pathological conditions.…”

Section: Functional Domains Of Tfpimentioning

confidence: 99%

Regulation of Functions of Vascular Wall Cells by Tissue Factor Pathway Inhibitor

Kato

2002

ATVB

143

View full text Add to dashboard Cite

Abstract-Tissue factor pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits the initial reactions of blood coagulation. A major pool of TFPI is the form associated with the surface of endothelial cells, which is speculated to play an important role in regulating the functions of vascular wall cells. TFPI consists of 3 tandem Kunitz inhibitor domains, the first and second of which inhibit the tissue factor-factor VIIa complex and factor Xa, respectively. Recent findings indicate that TFPI has another function, ie, the modulation of cell proliferation. This function is based on the interaction of the C-terminal region of TFPI with these cells. Key Words: tissue factor pathway inhibitor Ⅲ blood coagulation Ⅲ thrombosis Ⅲ restenosis Ⅲ vascular wall cells B lood coagulation is initiated by the interaction of factor VII in plasma with tissue factor (TF) at the site of blood vessel injury, and the TF-factor VIIa complex activates factor X and factor IX, leading to the generation of thrombin. Vascular wall cells play a central role in the regulation of hemostasis by the cellular control of procoagulant and anticoagulant mechanisms. Normal endothelial cells do not show detectable levels of TF, although expression of endothelial TF occurs in vitro after perturbation with different agonists. On the other hand, increased TF levels have been detected in atherosclerotic plaque, probably reflecting secretion by smooth muscle cells, monocytes/macrophages, and endothelial cells.The TF pathway inhibitor (TFPI) is a Kunitz-type protease inhibitor that inhibits the initial reactions of blood coagulation. A major pool of TFPI is the form associated with the surface of endothelial cells, which is speculated to play an important role in the regulation of the functions of vascular wall cells. Recent findings indicate that TFPI has another function, ie, the modulation of cell proliferation. Many reviews on TFPI have been published. [1][2][3][4][5] The structure and biology of TFPI have recently been reviewed. 6 Recent findings related to regulation of the functions of vascular wall cells by TFPI in physiological and pathological conditions will be summarized in the present review. Functional Domains of TFPIEver since the determination of the amino acid sequence of human TFPI 14 years ago, 7 a number of studies have been published on the structure and functions of TFPI. The amino acid sequences of TFPI from monkeys, rabbits, dogs, rats, and mice have been reported. Many investigators have examined the properties of TFPI by using recombinant proteins. As shown in Figure 1, TFPI mRNA is expressed from the TFPI gene, which consists of 9 exons. Mature TFPI protein consists of 3 tandem Kunitz inhibitor domains, the first and second of which inhibit TF-VIIa and Xa, respectively. The third domain has no inhibitory activity toward proteases. Heparin-binding sites of TFPI are located in the third Kunitz domain and the C-terminal basic region. The inhibitory effect of TFPI on the initiation of blood coagulation and the enhanc...

show abstract

Factor Xa Cleavage of Tissue Factor Pathway Inhibitor Is Associated with Loss of Anticoagulant Activity

Cited by 27 publications

References 39 publications

Activated protein C up-regulates procoagulant tissue factor activity on endothelial cells by shedding the TFPI Kunitz 1 domain

Activated protein C up-regulates procoagulant tissue factor activity on endothelial cells by shedding the TFPI Kunitz 1 domain

The Haemostatic Role of Tissue Factor Pathway Inhibitor

Regulation of Functions of Vascular Wall Cells by Tissue Factor Pathway Inhibitor

Contact Info

Product

Resources

About