Factor VIIa-antithrombin complexes in patients with arterial and venous thrombosis

Abstract

Antithrombin (AT), in the presence of heparin, is able to inhibit the catalytic activity of factor VIIa bound to tissue factor (TF) on cell surfaces. The clinical meaning of FVIIa-AT complexes plasma levels is unknown. It was the objective of this study to evaluate FVIIa-AT complexes in subjects with thrombosis. Factor VIIa-AT complexes plasma levels in 154 patients consecutively referred to our Department with arterial or venous thrombosis and in a group of 154 healthy subjects, were measured. Moreover, FVIIa-AT complexes were determined in: i) n = 53 subjects belonging to 10 families with inherited factor VII deficiency; ii) n = 58 subjects belonging to seven families with AT deficiency; iii) n = 49 patients undergoing oral anticoagulant therapy (OAT). Factor VIIa-AT levels were determined by a specific ELISA kit (R&D, Diagnostica Stago, Gennevilliers, France). Factor VIIa-AT complexes mean plasma levels were lower in patients with either acute arterial (136 +/- 40 pM) or venous (142 +/- 53 pM) thrombosis than subjects with previous thrombosis (arterial 164 +/- 33 pM and venous 172 +/- 61 pM, respectively) and than healthy controls (156 +/- 63 pM). Differences between acute and previous thrombosis, were statistically significant (p < 0.05). Subjects with inherited and acquired (under OAT) factor VII deficiency had statistically significant lower FVIIa-AT complexes plasma levels (80 +/- 23 pM and 55 +/- 22 pM, respectively) than controls (150 +/- 51 pM, p < 0.0001 and 156 +/- 63 pM, p < 0.00001, respectively). Factor VIIa-AT complexes are positively correlated with plasma factor VII/VIIa levels. Further investigations are needed to verify the possible role of higher FVIIa-AT complex plasma levels in predicting hypercoagulable states and thrombosis.

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

“…Once the VIIa-TF complex is formed, the binding and transfer of VIIa to AT is facilitated and VIIa activity inhibited. These mechanisms elucidated in vitro are in line with the finding that VIIaAT is elevated in plasma of patients with a previous thrombotic event (Spiezia et al (9) and the present study), because the presence of TF protein and TF synthesizing cells have been demonstrated in atherosclerotic plaques, protein expression and cell number being higher in specimens from patients with previous MI and unstable angina as compared to specimens obtained from patients with stable angina (15,16). Also, elevated levels of circulating TF have been reported in patients who have presented with acute coronary syndrome (17) and in patients with unstable angina (18).…”

“…Depending on the slightly lower VIIag in the patients, the calculated VIIaAT/VIIag ratio (or proportion of total factor VII mass represented by the complex) was a better patient-control discriminator. Although these case-control differences may be considered subtle, they constitute novel observations, which extend the findings of Spezia et al (9) associating elevated plasma VIIaAT with previous occurrence of arterial thrombosis in a smaller group of 45 CVD cases, of whom 26 had suffered MI, since the present results were generated in a different experimental setting and comprised a total of 200 post-infarction patients and 340 controls. The question then arose of whether determination of VIIaAT in individuals free of symptoms and signs of CVD can predict future cardiovascular events.…”

“…This process suggests that a relationship may exist between the plasma VIIaAT concentration and the degree of intravascular exposure of TF, which might have clinical relevance. To address this question, Spiezia et al have recently explored the plasma VIIaAT concentration in relation to arterial and venous thrombosis (9). They observed that individuals with a previous thrombotic event tended to have higher plasma VIIa-AT levels than patients with either acute arterial or venous thrombosis, or healthy controls, and VII/VIIa was found to be the main determinant of VIIaAT (9).…”

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].…”

Non-neoplastic portal vein thrombosis in HCV cirrhosis: the weight of inflammation on a fragile hemostatic balance

“…First, they confirmed the futility of standard coagulation tests to evaluate the hemostatic balance in cirrhosis, indeed no INR differences were detected between PVT and non-PVT group. Second, they found reduced levels of pro-coagulant factor VII in cirrhosis, as expected for the advanced liver disease (1), and, in both cirrhoticand non-cirrhotic-PVT patients, found an increasing trend of FVII-AT complexes, which are considered markers of Editorial Non-neoplastic portal vein thrombosis in HCV cirrhosis: the weight of inflammation on a fragile hemostatic balance Niccolò Bitto 1 endogenous activated coagulation (12). To evaluate the potential role of inflammatory stimuli in PVT development, they focused on microparticles analysis, particularly on monocytic tissue factor (TF).…”