Direct inhibition of factor VIIa by TFPI and TFPI constructs

Peraramelli, Sameera; Thomassen, M. Christella L. G. D.; Heinzmann, Alexandra C.A.; Rosing, Jan; Hackeng, Tilman M.; Hartmann, Rudolf; Scheiflinger, F.; Dockal, Michael

doi:10.1111/jth.12152

Cited by 21 publications

(23 citation statements)

References 52 publications

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“…Ndonwi and Broze reported that protein S does not directly stimulate TFPIα inhibition of TF/FVIIa whereas Peraramelli et al showed that protein S does directly stimulate inhibition of TF/FVIIa and thereby also inhibits the activation of FIX by TF/FVIIa. [36][37][38] Whether FV-Short affects these reactions remains to be elucidated. Protein S may also function as a carrier for TFPIα because protein S deficient individuals have low TFPIα and furthermore immune depletion of protein S is reported to results in decreased TFPIα.…”

Section: Fv-short Binds Tfpiα With High Affinity and Through Mechanismsmentioning

confidence: 99%

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Dahlbäck

Guo

Livaja-Koshiar

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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Essentials FV‐Short, a normal splice isoform of Factor V, binds tissue factor pathway inhibitor (TFPIα) with high affinity.FV‐Short functions as a synergistic TFPIα cofactor with protein S in inhibition of Factor Xa.FV‐Short is much more efficient as TFPIα cofactor than full length FV.TFPIα‐cofactor activity of FV‐Short is lost upon activation of coagulation by thrombin‐mediated cleavage. Background FV‐Short is a normal splice variant of Factor V (FV) having a short B domain, which exposes a high affinity‐binding site for tissue factor pathway inhibitor α (TFPIα). FV‐Short and TFPIα circulate in complex in plasma.ObjectivesThe aim was to elucidate whether FV‐Short affects TFPIα as inhibitor of coagulation FXa and to test whether the TFPIα‐cofactor activity of protein S is influenced by FV‐Short.MethodsRecombinant FV, wild‐type FV‐Short and a FV‐Short thrombin‐cleavage resistant variant were expressed and purified. The influence of FV and FV‐Short variants and/or protein S on the FXa inhibitory activity of TFPIα was monitored both in a purified system and in a plasma‐based thrombin generation assay.Results FV‐Short had intrinsically weak TFPIα‐cofactor activity but with protein S present, FV‐Short yielded efficient inactivation of FXa. Protein S alone did not promote full TFPIα‐activity. Intact FV was inefficient at low protein S concentrations and had 10‐fold lower activity compared to FV‐Short at physiological protein S levels. Activation of FV‐Short by thrombin resulted in the loss of the TFPIα‐cofactor activity. The synergistic TFPIα‐cofactor activity of FV‐Short and protein S was also demonstrated in plasma using a thrombin generation assay.Conclusions FV‐Short and protein S are highly efficient, synergistic cofactors to TFPIα in the regulation of FXa activity, whereas full length FV has lower activity. Our results suggest the formation of an efficient FXa‐inhibitory complex between FV‐Short, TFPIα and protein S on the surface of negatively charged phospholipids.

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Section: Fv-short Binds Tfpiα With High Affinity and Through Mechanismsmentioning

confidence: 99%

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Dahlbäck

Guo

Livaja-Koshiar

et al. 2018

Research and Practice in Thrombosis and Haemostasis

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“…69 In the absence of FXa, protein S is also a cofactor in the direct inhibition of TF-FVIIa by TFPI. 70 Binding of TFPI to protein S requires K3, with Arg199 and Glu226 of K3 identified as critical for this inhibition. 71,72 As such, protein S is a cofactor for TFPIα, but not TFPIβ, 73 and is hypothesized to localize TFPIα to membrane surfaces 73 to allow optimal interaction with FXa.…”

Section: Recent Advancesmentioning

confidence: 99%

Tissue Factor Pathway Inhibitor: Then and Now

Ellery

Adams

2014

Semin Thromb Hemost

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Tissue factor pathway inhibitor (TFPI) is the major physiological regulator of tissue factor (TF)-induced blood coagulation. TFPI inhibits the TF-activated factor VII (FVIIa) complex in an activated factor X (FXa)-dependent manner, helping to control thrombin generation and ultimately fibrin formation. The importance of TFPI is demonstrated in models of hemophilia where lower levels of FVIII or FIX are insufficient to overcome its inhibitory effect, resulting in a bleeding phenotype. There are two major isoforms in vivo; TFPIα contains three Kunitz-type inhibitory domains (designated K1, K2, and K3), is secreted by endothelial cells and requires protein S to enhance its anticoagulant activity. In contrast, TFPIβ contains only the K1 and K2 domains, but it is attached to the endothelial surface via a glycosylphosphatidylinositol anchor. This review will initially provide a brief history of the major discoveries related to TFPI, and then discuss new insights into the physiology of TFPI, including updates on its association with protein S and FV, as well as the current understanding of its association with disease.

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“…69 TFPI-antagonist peptides have been designed and have demonstrated hemostatic efficacy in vitro and in vivo in mouse models. 68,[70][71][72] Each type of inhibitor of TFPI provides unique advantages and interactions with clotting factors. There is some concern that inhibition of TFPI by certain inhibitor types may worsen bleeding tendencies.…”

Section: Inhibition Of Tissue Factor Pathway Inhibitormentioning

confidence: 99%

Lasting power of new clotting proteins

Powell

2014

Hematology

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Hemophilia is a genetic disease caused by a deficiency of one of the coagulation proteins. The term usually refers to either hemophilia A, factor VIII (FVIII), with an incidence of ϳ1 in 5000 male births, or hemophilia B, factor IX (FIX), with an incidence of ϳ1 in 30 000 male births. When severe, the disease leads to spontaneous life-threatening bleeding episodes. Current therapy requires frequent intravenous infusions of therapeutic factor concentrates. Most patients administer the infusions at home every few days and must limit their physical activities to avoid bleeding when the factor activity levels are below normal. In March 2014, a new therapeutic FIX preparation was approved for clinical use in Canada and the United States and, in June 2014, a new FVIII preparation was approved for clinical use in the United States. Over the next couple of years, other new factor products for FIX, FVIIa, and FVIII, which are currently in late stages of clinical trials, will likely also be approved. These new factors have been engineered to extend their half-life in circulation, thus providing major therapeutic advances for patients with hemophilia primarily by allowing treatment with fewer infusions per month. In the clinical trials so far, Ͼ500 patients have successfully used these extended half-life products regularly for Ͼ1 year to prevent spontaneous bleeding, to treat successfully any bleeding episodes, and to provide effective coagulation for major surgery. Essentially all infusions were well tolerated and effective. These promising new therapies should allow patients to use fewer infusions to maintain appropriate clotting factor activity levels in all clinical settings. Learning Objective• To be able to identify the new extended t 1/2 products for hemophilia A, B, and inhibitors and to understand the differences found to date between these products in clinical and preclinical studies

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Direct inhibition of factor VIIa by TFPI and TFPI constructs

Cited by 21 publications

References 52 publications

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Factor V‐short and protein S as synergistic tissue factor pathway inhibitor (TFPIα) cofactors

Tissue Factor Pathway Inhibitor: Then and Now

Lasting power of new clotting proteins

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