Incomplete gamma carboxylation of human coagulation factor VII: differential effects on tissue factor binding and enzymatic activity

Clarke, Bryan J.; Sridhara, Sampath

doi:10.1046/j.1365-2141.1996.5141054.x

Cited by 9 publications

(7 citation statements)

References 17 publications

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“…Human factor VII synthesized in monkey cells grown in the absence of vitamin K expressed Ͻ20% of the expected procoagulant activity for factor VII yet retained 65% of its binding capacity to a recombinant human tissue factor. 22 Similar results were obtained in human cell cultures that permanently express factor VII. 22 When these human cells were exposed to vitamin K, there was resultant full expression of functional factor VII.…”

Section: Effects Of Vitamin K Deficiency On Coagulationsupporting

confidence: 82%

“…22 Similar results were obtained in human cell cultures that permanently express factor VII. 22 When these human cells were exposed to vitamin K, there was resultant full expression of functional factor VII. Similar results were found in 24 patients undergoing warfarin therapy where the tissue binding was quantitatively normal but the procoagulant activity was 65% of normal.…”

Section: Effects Of Vitamin K Deficiency On Coagulationsupporting

confidence: 82%

“…Similar results were found in 24 patients undergoing warfarin therapy where the tissue binding was quantitatively normal but the procoagulant activity was 65% of normal. 22 Decrease to 9 GLA residues from the fully carboxylated forms containing 10 to 13 GLAs reduces their activity about 30% but without changing the prothrombin time. If there are fewer than 6 GLA residues, coagulant activity is reduced 95%.…”

Section: Effects Of Vitamin K Deficiency On Coagulationmentioning

confidence: 99%

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Observations on Possible Effects of Daily Vitamin K Replacement, Especially Upon Warfarin Therapy

Bern

2004

J Parenter Enteral Nutr

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Daily parenteral vitamin K supplement is now recommended by the U.S. Food and Drug Administration (FDA) for patients receiving IV hyperalimentation. This is considered as preferable to the previous recommendations of weekly parenteral or oral supplement, or as in some cases no supplement at all. Supplemental vitamin K1 will ensure adequate supplies for hepatic saturation and thus the production of clotting factors II, VII, IX, and X, plus the anticoagulants protein C, protein S, and protein Z. But this is not the entire story. This recommended supplement will affect other physiologic systems that also use vitamin K-dependent gamma-carboxylation. Vitamin K is not 1 molecule but rather 2 natural substances, vitamin K1 and K2, and the synthetic K3's. It is not understood, what, if any, effect may occur because of the saturation or competition from the vitamin K1 upon the functioning of vitamins K2 and the derivatives of K3 in vivo upon bone mineralization, cell growth, and blood vessel health, all known to be influenced by the vitamins K. There are probably other physiologic systems yet to be studied relative to vitamins K and gamma-carboxylation. This review also considers the available research upon warfarin when given to patients receiving hyperalimentation and what effects the vitamin K supplements may have. Because studies to date have not controlled for vitamin K intake, consideration is given to whether one should expect any change in previously reported outcomes when using low-dose warfarin for prophylaxis against central vein thrombosis. Also considered are possible positive or negative effects that chronic warfarin therapy may have upon the other vitamin K-dependent systems under discussion. This review offers a platform for further discussion and derived clinical research provoked by this new FDA recommendation.

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Section: Effects Of Vitamin K Deficiency On Coagulationsupporting

confidence: 82%

Section: Effects Of Vitamin K Deficiency On Coagulationsupporting

confidence: 82%

Section: Effects Of Vitamin K Deficiency On Coagulationmentioning

confidence: 99%

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Observations on Possible Effects of Daily Vitamin K Replacement, Especially Upon Warfarin Therapy

Bern

2004

J Parenter Enteral Nutr

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“…A possible defect in post-translational modifications of Glu residues in the Gla domain is very unlikely to be responsible for affecting TF binding to the extent seen, since under-carboxylated FVIIa binds TF similarly to wild-type FVIIa (27) and des-Gla FVIIa shows only a 7-fold increase in K D of sTF binding (28); in any case gamma-carboxylation in Q100RFVII appeared normal as assessed by amino acid sequencing.…”

Section: Discussionmentioning

confidence: 99%

Coagulation Factor VII Gln100 → Arg

Kemball‐Cook¹,

Johnson²,

Takahashi³

et al. 1998

Journal of Biological Chemistry

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We have used recombinant mammalian expression and purification of the factor VII (FVII) variant Gln 100 3 Arg (Q100RFVII) to study FVII deficiency in subjects with this mutation. Q100RFVII was secreted poorly in comparison with wild-type FVII (WTFVII) in a stable mammalian expression system, and purified variant protein was found to have undetectable clotting activity. Following activation by immobilized factor Xa, Q100RFVIIa had amidolytic activity similar to WTFVIIa in the absence of soluble tissue factor (sTF); however, unlike WTFVIIa no typical increase in activity was seen after addition of sTF. In a factor X activation assay using relipidated transmembrane truncated tissue factor (residues 1-243), Q100RFVIIa showed less than 5% of the ability of WTFVIIa to activate factor X.We performed direct binding analysis of WT and Q100RFVII/FVIIa to immobilized sTF using surface plasmon resonance, and severely reduced binding of both non-activated and activated Q100RFVII to sTF was seen, indicating a pronounced defect in tissue factor (TF) interaction with this variant.In the sTF-FVIIa crystal structure the candidate residue Gln 100 is not in contact with TF but is at the epidermal growth factor 2-protease domain interface. We suggest that the mutation results in a global fold change severely reducing tissue factor interaction; mutation of FVII residues not directly involved in the interaction with TF may still result in variant FVII unable to take part in the initiation of coagulation.

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“…In antagonizing the post‐translational conversion of glutamate residues to gamma‐carboxyglutamate, coumarin therapy results in the undercarboxylation of glutamate residues in the Gla domains of the vitamin K‐dependent clotting factors. These undercarboxylated proteins will have reduced affinity for phospholipid membranes, since the Gla domain confers upon them the ability to bind reversibly to membranes containing negatively charged phospholipids [23–26]. Limiting the amount of PS in the thromboplastin reagent should therefore exaggerate the difference in binding affinity between fully carboxylated and undercarboxylated vitamin K‐dependent clotting factors for phospholipid surfaces.…”

Section: Discussionmentioning

confidence: 99%

Properties of recombinant human thromboplastin that determine the International Sensitivity Index (ISI)

Smith

Morrissey

2004

Journal of Thrombosis and Haemostasis

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Summary. Prothrombin Time (PT) clotting tests are widely used to monitor oral anticoagulation therapy and to screen for clotting factor deficiencies. The active ingredient in PT reagents (thromboplastins) is tissue factor, the integral membrane protein that triggers the clotting cascade through the extrinsic pathway. Several years ago, a system for calibrating and using thromboplastin reagents, known as the International Sensitivity Index (ISI) and the International Normalized Ratio (INR), was developed to standardize monitoring of oral anticoagulant therapy. The ISI/INR method, while revolutionizing the monitoring of coumarin therapy, has been criticized for a number of perceived shortcomings. We have undertaken a series of studies aimed at achieving a detailed understanding of which parameters influence the ISI values of thromboplastin reagents, with an ultimate goal of creating Ôdesigner thromboplastinsÕ whose sensitivities to the various clotting factors can be individually tailored. In this study, we demonstrate that ISI values of thromboplastin reagents based on relipidated, recombinant human tissue factor can be controlled by a combination of changes in the phospholipid content (in particular, the levels of phosphatidylserine and phosphatidylethanolamine) and ionic strength. The sensitivity of a given thromboplastin reagent can be increased (i.e. its ISI value decreased) by decreasing the content of phosphatidylserine and/ or increasing the ionic strength. The molar ratio of phospholipid to tissue factor, on the other hand, had essentially no impact on ISI value.

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Incomplete gamma carboxylation of human coagulation factor VII: differential effects on tissue factor binding and enzymatic activity

Cited by 9 publications

References 17 publications

Observations on Possible Effects of Daily Vitamin K Replacement, Especially Upon Warfarin Therapy

Observations on Possible Effects of Daily Vitamin K Replacement, Especially Upon Warfarin Therapy

Coagulation Factor VII Gln100 → Arg

Properties of recombinant human thromboplastin that determine the International Sensitivity Index (ISI)

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