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

Abstract

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.

VIIaAT complexes, procoagulant phospholipids, and thrombin generation during postprandial lipemia

“…Age‐ and sex‐matched controls were recruited in parallel from the general population of the same catchment area. Details of protocol, inclusion/exclusion criteria, general study features, analytical methods, and baseline characteristics including VIIaAT concentration have been published . This study includes SCARF samples from 108 male cases and 109 male controls who were not treated with lipid‐lowering drugs or anticoagulants at the time of blood sampling and from whom stored citrate plasma samples were available.…”

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

“…Therefore, a number of recent studies measured plasma FVIIa-AT levels in various patient groups to investigate whether FVIIa-AT levels in plasma could predict hypercoagulable state and thrombotic risk [15]–[18]. Although these studies indicate that the FVIIa-AT levels may be useful in identifying hypercoagulable state in specific patient groups, they strongly suggest that large prospective cohort studies were needed to consider the clinical application of FVIIa-AT complex determination [17].…”

Lack of association between potential prothrombotic genetic risk factors and arterial and venous thrombosis

“…Studies have associated this polymorphism with high levels of TF and increased risk of thrombotic events, and have been used to predict future events (Opstad et al, 2010b;Eroğlu et al, 2010;Silveira et al, 2012). Thus, polymorphisms linked to these coagulation factors cause an inappropriate expression of their genes and can predispose to thrombotic events (Litzendorf and Satiani, 2011).…”

“…However, it is important to note that factor VII bound to TF undergoes selfactivation. Only the TF/FVIIa complex is active (Mitrophanov and Reifman, 2011;Silveira et al, 2012;Mercer and Chambers, 2013). This complex can activate blood clotting in two ways: activation of factor IX by proteolysis, and direct activation of factor X, which seems to be the predominant mechanism in in vitro studies.…”

“…These two pathways initiate reactions leading to the formation of fibrin at the site of endothelial injury (Hoffman, 2003;Mercer and Chambers, 2013). Several experimental and clinical studies have clearly demonstrated that the TF/FVIIa complex is the initiator of the coagulation cascade in cardiovascular disease (Petrillo et al, 2010;Silveira et al, 2012).…”