Activated factor VII: presence in factor IX concentrates and persistence in the circulation after infusion

Seligsohn, Uri; Kasper, CK; Østerud, Bjarne; Rapaport, SI

doi:10.1182/blood.v53.5.828.828

Cited by 148 publications

(45 citation statements)

References 17 publications

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“…Factor VII concentration in normal plasma is about 450 mg/L (Fair, 1983), the major proportion of which circulates in the zymogen single-chain form. About 1% of the total factor VII mass is, however, present in the active double-chain form and serve a priming function for triggering of the clotting cascade (Morrissey et al, 1993;Wildgoose et al, 1992;Seligsohn et al, 1979). Factor VIIa bound to its receptor and allosteric regulator tissue factor (TF) initiates blood coagulation by activating factors IX and X (Bauer et al, 1990;ésterud and Rapaport, 1977;ten Cate et al, 1993).…”

Section: Coagulation Factor VII and How It Is Affected By Postprandiamentioning

confidence: 99%

Postprandial triglycerides and blood coagulation

Silveira¹

2001

Exp Clin Endocrinol Diabetes

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Most of our lifetime we spend in the postprandial state. Postprandial triglyceridemia may represent a procoagulant state involving disturbances of both blood coagulation and fibrinolysis, in particular due to elevation of the plasma levels of activated factor VII (VIIa) and plasminogen activator inhibitor (PAI-1). Therefore, disturbances of the hemostatic system might, at least partly, account for by the link between hypertriglyceridemia and coronary heart disease (CHD). Factor VIIa is the first enzyme of the blood coagulation system and serves a priming function for triggering of the clotting cascade. The coagulant activity of factor VII (VIIc, total activity of factor VII in plasma) was identified as an independent predictor of myocardial infarction in initially healthy middle-aged men, and particularly of fatal coronary events, and both serum cholesterol and triglyceride concentrations correlated positively with the VIIc level. Addition of fat to diet has been consistently shown to cause a rapid conversion of the factor VII zymogen into its active form (VIIa) whereas the concentration of total protein is unaffected. Postprandial activation of factor VII is dependent on lipolytic activity and it is mainly supported by large triglyceride-rich lipoprotein of the VLDL class. Studies in vivo with specific coagulation factor-deficient patients indicate that factor IX is essential for the postprandial activation of factor VII. The basal generation of thrombin seems to be unaffected by increased plasma levels of VIIa. However, since VIIa-tissue factor complex is responsible for the initiation of the coagulation cascade, increased generation of VIIa in the postprandial state would increase the potential for thrombin production in the event of plaque rupture. Plasminogen activator inhibitor-1 (PAI-1) is the major physiological inhibitor of the plasminogen activators in the circulation and thereby the principal inhibitor of the fibrinolytic system. Postprandial triglyceridemia has been observed in many, not all, studies to increase PAI-1 plasma levels, which would further strengthen the chances of thrombotic occlusion of a vessel after rupture of an atherosclerotic plaque.

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Section: Coagulation Factor VII and How It Is Affected By Postprandiamentioning

confidence: 99%

Postprandial triglycerides and blood coagulation

Silveira¹

2001

Exp Clin Endocrinol Diabetes

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“…Normally, the coagulation factors get activated after release of the tissue factor after any injury to the vascular endothelium. PCCs containing activated factors are associated with an increased risk of thrombosis . It was demonstrated that the mere presence of heparin was not sufficient to reduce the thrombogenic potential of a PCC, and addition of antithrombin III reduced the thrombogenic potential of a PCC known to cause thrombosis .…”

Section: Discussionmentioning

confidence: 99%

Pathogen safety of a pasteurized four‐factor human prothrombin complex concentrate preparation using serial 20N virus filtration

et al. 2017

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BACKGROUND Beriplex P/N/Kcentra/Coaplex/Confidex is a four‐factor human prothrombin complex concentrate (PCC). Here, we describe the pathogen safety profile and biochemical characteristics of an improved manufacturing process that further enhances the virus safety of Beriplex P/N. STUDY DESIGN AND METHODS Samples of product intermediates were spiked with test viruses, and prions were evaluated under routine production and robustness conditions of the scale‐down version of the commercial manufacturing process for their capacity to inactivate or remove pathogens. The PCC was characterized by determining the activity of Factor (F)II, FVII, FIX, FX, protein C, and protein S and the concentration of heparin and antithrombin III in nine product lots. RESULTS The manufacturing process had a very high virus reduction capacity for a broad variety of virus challenges (overall reduction factors ≥15.5 to ≥18.4 log for enveloped viruses and 11.5 to ≥11.9 log for nonenveloped viruses). The high virus clearance capacity was provided by two dedicated virus reduction steps (pasteurization and serial 20N virus filtration) that provided effective inactivation and removal of viruses and a purification step (ammonium sulfate precipitation and adsorption to calcium phosphate) that contributed to the overall virus removal capacity. The diethylaminoethyl (DEAE) chromatography and ammonium sulfate precipitation steps removed prions to below the limit of detection. The levels of different clotting factors in the final product were well balanced. CONCLUSION The improved manufacturing process of Beriplex P/N further enhances the margin of pathogen safety based on its capacity to remove and inactivate a wide range of virus challenges.

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“…52 As a result, FVIIa circulates in a zymogen-like state that is poorly recognized by plasma protease inhibitors, 52 allowing it to circulate with a half-life of 90 minutes. 10,11 This is far longer than other coagulation enzymes such as FIXa, FXa, and thrombin, whose plasma half-lives are of the order of seconds to minutes. 53,54…”

Section: Structure Tissue Factormentioning

confidence: 99%

Structure–Function Relationship of the Interaction between Tissue Factor and Factor VIIa

Gajsiewicz

Morrissey

2015

Semin Thromb Hemost

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Interactions between tissue factor and factor VIIa are the primary initiators of coagulation in hemostasis and certain thrombotic diseases. Tissue factor, an integral membrane protein expressed extensively outside of the vasculature, is the regulatory protein cofactor for coagulation factor VIIa. Factor VIIa, a trypsin-like serine protease homologous with other blood coagulation proteases, is weakly active when free in solution and must bind its membrane-bound cofactor for physiologically-relevant activity. Tissue factor allosterically activates factor VIIa by several mechanisms such as active site positioning, spatial stabilization, and direct interactions with the substrate. Protein-membrane interactions between tissue factor, factor VIIa, and substrates all play critical roles in modulating the activity of this enzyme complex. Additionally, divalent cations such as Ca2+ and Mg2+ are critical for correct protein folding, as well as protein-membrane and protein-protein interactions. The contributions of these factors towards tissue factor-factor VIIa activity are discussed in this review.

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Activated factor VII: presence in factor IX concentrates and persistence in the circulation after infusion

Cited by 148 publications

References 17 publications

Postprandial triglycerides and blood coagulation

Postprandial triglycerides and blood coagulation

Pathogen safety of a pasteurized four‐factor human prothrombin complex concentrate preparation using serial 20N virus filtration

Structure–Function Relationship of the Interaction between Tissue Factor and Factor VIIa

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