Plasma elimination kinetics for factor VII are independent of its activation to factor VIIa and complex formation with plasma inhibitors

Petersen, Lars C.; Elm, Torben; Ezban, Mirella; Krogh, Thomas N.; Karpf, Ditte M.; Steinø, Anne; Olsen, Eva H. N.; Sørensen, Brit B.

doi:10.1160/th08-10-0699

Cited by 22 publications

(16 citation statements)

References 22 publications

(32 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Although TF contributes to the formation of rFVIIa-AT complex in vivo, it does not appear to influence the overall pharmacokinetics of rFVIIa as rFVIIa was cleared in a similar fashion in low TF and HTF mice. These data were also consistent with the earlier observation that showed clearance of FVIIa was unaffected by its inactivation with AT [41]. The observation that rFVIIa-AT complex formation was impeded, but not markedly impaired in low TF mice indicates that TF plays probably a minor role in FVIIa inactivation by AT in vivo.…”

Section: Discussionsupporting

confidence: 92%

Inactivation of Factor VIIa by Antithrombin In Vitro, Ex Vivo and In Vivo: Role of Tissue Factor and Endothelial Cell Protein C Receptor

et al. 2014

View full text Add to dashboard Cite

Recent studies have suggested that antithrombin (AT) could act as a significant physiologic regulator of FVIIa. However, in vitro studies showed that AT could inhibit FVIIa effectively only when it was bound to tissue factor (TF). Circulating blood is known to contain only traces of TF, at best. FVIIa also binds endothelial cell protein C receptor (EPCR), but the role of EPCR on FVIIa inactivation by AT is unknown. The present study was designed to investigate the role of TF and EPCR in inactivation of FVIIa by AT in vivo. Low human TF mice (low TF, ∼1% expression of the mouse TF level) and high human TF mice (HTF, ∼100% of the mouse TF level) were injected with human rFVIIa (120 µg kg−1 body weight) via the tail vein. At varying time intervals following rFVIIa administration, blood was collected to measure FVIIa-AT complex and rFVIIa antigen levels in the plasma. Despite the large difference in TF expression in the mice, HTF mice generated only 40–50% more of FVIIa-AT complex as compared to low TF mice. Increasing the concentration of TF in vivo in HTF mice by LPS injection increased the levels of FVIIa-AT complexes by about 25%. No significant differences were found in FVIIa-AT levels among wild-type, EPCR-deficient, and EPCR-overexpressing mice. The levels of FVIIa-AT complex formed in vitro and ex vivo were much lower than that was found in vivo. In summary, our results suggest that traces of TF that may be present in circulating blood or extravascular TF that is transiently exposed during normal vessel damage contributes to inactivation of FVIIa by AT in circulation. However, TF’s role in AT inactivation of FVIIa appears to be minor and other factor(s) present in plasma, on blood cells or vascular endothelium may play a predominant role in this process.

show abstract

Section: Discussionsupporting

confidence: 92%

Inactivation of Factor VIIa by Antithrombin In Vitro, Ex Vivo and In Vivo: Role of Tissue Factor and Endothelial Cell Protein C Receptor

et al. 2014

View full text Add to dashboard Cite

show abstract

“…It may be pertinent to note here that FVIIa and APC have similar molecular masses (50 kDa and 55 kDa, respectively) and circulatory half-lives in mice (~ 20–25 min) [2,17,18]. Therefore, it is unlikely that similar doses of these proteins would result in widely differing in vivo concentrations.…”

Section: Discussionmentioning

confidence: 99%

Factor VIIa binding to endothelial cell protein C receptor protects vascular barrier integrity in vivo

Sundaram

Keshava

Gopalakrishnan

et al. 2014

Journal of Thrombosis and Haemostasis

View full text Add to dashboard Cite

Summary Background Recent studies have shown that factor VIIa binds to endothelial cell protein C receptor (EPCR), a cellular receptor for protein C and activated protein C. At present, the physiologic significance of FVIIa interaction with EPCR in vivo remains unclear. Objective: To investigate whether exogenously administered FVIIa, by binding to EPCR, induces a barrier protective effect in vivo. Methods Lipopolysaccharide (LPS)-induced vascular leakage in the lung and kidney, and vascular endothelial growth factor (VEGF)-induced vascular leakage in the skin, were used to evaluate the FVIIa-induced barrier protective effect. Wild-type, EPCR-deficient, EPCR-overexpressing and hemophilia A mice were used in the studies. Results Administration of FVIIa reduced LPS-induced vascular leakage in the lung and kidney; the FVIIa-induced barrier protective effect was attenuated in EPCR-deficient mice. The extent of VEGF-induced vascular leakage in the skin was highly dependent on EPCR expression levels. Therapeutic concentrations of FVIIa attenuated VEGF-induced vascular leakage in control mice but not in EPCR-deficient mice. Blockade of FVIIa binding to EPCR with a blocking mAb completely attenuated the FVIIa-induced barrier protective effect. Similarly, administration of protease-activated receptor 1 antagonist blocked the FVIIa-induced barrier protective effect. Hemophilic mice showed increased vascular permeability, and administration of therapeutic concentrations of FVIIa improved barrier integrity in these mice. Conclusions This is the first study to demonstrate that FVIIa binding to EPCR leads to a barrier protective effect in vivo. This finding may have clinical relevance, as it indicates additional advantages of using FVIIa in treating hemophilic patients.

show abstract

“…Secondly, VIIaAT should constitute a global marker of factor VII turnover on TF exposure, because the sum of VIIaAT+VIIa encompasses total VIIa (the active and inactive forms of VIIa) generated in vivo . Finally, evidence is emerging for VIIaAT formation as an important mechanism for the elimination of factor VII(VIIa) from the circulation (23). …”

Section: Discussionmentioning

confidence: 99%

Relationships of plasma factor VIIa-antithrombin complexes to manifest and future cardiovascular disease

Silveira

Scanavini

Boquist

et al. 2012

Thrombosis Research

View full text Add to dashboard Cite

Background Low levels of free activated coagulation factor VII (VIIa) are normally present in plasma to prime the coagulation of blood in normal hemostasis and during thrombus formation. VIIa also circulates in inactive form, in complex with antithrombin (VIIaAT) formed when VIIa is bound to tissue factor (TF). This study evaluated VIIaAT in relation to cardiovascular disease (CVD). Methods We determined the plasma VIIaAT concentration in samples from the Stockholm Coronary Atherosclerosis Risk Factor (SCARF) study, a population-based case-control study of myocardial infarction (MI) and in samples from the Stockholm study of 60-years-old individuals, a prospective study of CVD. VIIaAT was measured with a sandwich ELISA that captures the complex between a monoclonal antibody to VIIa and a polyclonal antibody to AT. Results In the SCARF study (200 post-MI cases, 340 controls), VIIaAT was statistically significantly associated with patient status [odds ratio (95% confidence interval (CI)] 1.51 (1.09–2.08), p=0.0126). The case-control differences were however small, with VIIaAT values that largely overlap between the two groups. When a nested case-control design (211 incident CVD cases and 633 matched controls) was applied on 5- to 7-year follow-up results of the Stockholm prospective study of 60-year-olds, plasma VIIaAT concentration was not associated with incident CVD (odds ratio (95% CI) 1.001 (0.997–1.005), p=0.5447). Conclusions Plasma VIIaAT concentration had no predictive value for future CVD in our study population. Slightly increased plasma VIIaAT concentrations observed after MI may reflect processes that occur in connection with the acute event when TF and VIIa availability is increased.

show abstract

Plasma elimination kinetics for factor VII are independent of its activation to factor VIIa and complex formation with plasma inhibitors

Cited by 22 publications

References 22 publications

Inactivation of Factor VIIa by Antithrombin In Vitro, Ex Vivo and In Vivo: Role of Tissue Factor and Endothelial Cell Protein C Receptor

Inactivation of Factor VIIa by Antithrombin In Vitro, Ex Vivo and In Vivo: Role of Tissue Factor and Endothelial Cell Protein C Receptor

Factor VIIa binding to endothelial cell protein C receptor protects vascular barrier integrity in vivo

Relationships of plasma factor VIIa-antithrombin complexes to manifest and future cardiovascular disease

Contact Info

Product

Resources

About